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  • Correction
    Oncoimmunology (IF 5.333) Pub Date : 2019-12-14

    (2019). Correction. OncoImmunology. Ahead of Print.

    更新日期:2019-12-17
  • A pipeline for identification and validation of tumor-specific antigens in a mouse model of metastatic breast cancer
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-29
    Christa I. DeVette, Harika Gundlapalli, Shu-Chin Alicia Lai, Curtis P. McMurtrey, Ashley R. Hoover, Hem R. Gurung, Wei R. Chen, Alana L. Welm, William H. Hildebrand

    ABSTRACT Cancer immunotherapy continues to make headway as a treatment for advanced stage tumors, revealing an urgent need to understand the fundamentals of anti-tumor immune responses. Noteworthy is a scarcity of data pertaining to the breadth and specificity of tumor-specific T cell responses in metastatic breast cancer. Autochthonous transgenic models of breast cancer display spontaneous metastasis in the FVB/NJ mouse strain, yet a lack of knowledge regarding tumor-bound MHC/peptide immune epitopes in this mouse model limits the characterization of tumor-specific T cell responses, and the mechanisms that regulate T cell responses in the metastatic setting. We recently generated the NetH2pan prediction tool for murine class I MHC ligands by building an FVB/NJ H-2q ligand database and combining it with public information from six other murine MHC alleles. Here, we deployed NetH2pan in combination with an advanced proteomics workflow to identify immunogenic T cell epitopes in the MMTV-PyMT transgenic model for metastatic breast cancer. Five unique MHC I/PyMT epitopes were identified. These tumor-specific epitopes were confirmed to be presented by the class I MHC of primary MMTV-PyMT tumors and their T cell immunogenicity was validated. Vaccination using a DNA construct encoding a truncated PyMT protein generated CD8 + T cell responses to these MHC class I/peptide complexes and prevented tumor development. In sum, we have established an MHC-ligand discovery pipeline in FVB/NJ mice, identified and tracked H-2Dq/PyMT neoantigen-specific T cells, and developed a vaccine that prevents tumor development in this metastatic model of breast cancer.

    更新日期:2019-11-30
  • Preclinical evaluation of an affinity-enhanced MAGE-A4-specific T-cell receptor for adoptive T-cell therapy
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-24
    Joseph P Sanderson, Darragh J Crowley, Guy E Wiedermann, Laura L Quinn, Katherine L Crossland, Helen M Tunbridge, Terri V Cornforth, Christopher S Barnes, Tina Ahmed, Karen Howe, Manoj Saini, Rachel J Abbott, Victoria E Anderson, Barbara Tavano, Miguel Maroto, Andrew B Gerry

    ABSTRACT A substantial obstacle to the success of adoptive T cell-based cancer immunotherapy is the sub-optimal affinity of T-cell receptors (TCRs) for most tumor antigens. Genetically engineered TCRs that have enhanced affinity for specific tumor peptide-MHC complexes may overcome this barrier. However, this enhancement risks increasing weak TCR cross-reactivity to other antigens expressed by normal tissues, potentially leading to clinical toxicities. To reduce the risk of such adverse clinical outcomes, we have developed an extensive preclinical testing strategy, involving potency testing using 2D and 3D human cell cultures and primary tumor material, and safety testing using human primary cell and cell-line cross-reactivity screening and molecular analysis to predict peptides recognized by the affinity-enhanced TCR. Here, we describe this strategy using a developmental T-cell therapy, ADP-A2M4, which recognizes the HLA-A2-restricted MAGE-A4 peptide GVYDGREHTV. ADP-A2M4 demonstrated potent anti-tumor activity in the absence of major off-target cross-reactivity against a range of human primary cells and cell lines. Identification and characterization of peptides recognized by the affinity-enhanced TCR also revealed no cross-reactivity. These studies demonstrated that this TCR is highly potent and without major safety concerns, and as a result, this TCR is now being investigated in two clinical trials (NCT03132922, NCT04044768).

    更新日期:2019-11-26
  • Comedications influence immune infiltration and pathological response to neoadjuvant chemotherapy in breast cancer
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-14
    Anne-Sophie Hamy, Lisa Derosa, Constance Valdelièvre, Satoru Yonekura, Paule Opolon, Maël Priour, Julien Guerin, Jean-Yves Pierga, Bernard Asselain, Diane De Croze, Alice Pinheiro, Marick Lae, Laure-Sophie Talagrand, Enora Laas, Lauren Darrigues, Beatriz Grandal, Elisabetta Marangoni, Elodie Montaudon, Guido Kroemer, Laurence Zitvogel, Fabien Reyal

    ABSTRACT Immunosurveillance plays an important role in breast cancer (BC) prognosis and progression, and can be geared by immunogenic chemotherapy. In a cohort of 1023 BC patients treated with neoadjuvant chemotherapy (NAC), 40% of the individuals took comedications mostly linked to aging and comorbidities. We systematically analyzed the off-target effects of 1178 concurrent comedications (classified according to the Anatomical Therapeutic Chemical (ATC) Classification System) on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). At level 1 of the ATC system, the main anatomical classes of drugs were those targeting the nervous system (class N, 39.1%), cardiovascular disorders (class C, 26.6%), alimentary and metabolism (class A, 16.9%), or hormonal preparations (class H, 6.5%). At level 2, the most frequent therapeutic classes were psycholeptics (N05), analgesics (N02), and psychoanaleptics (N06). Pre-NAC TIL density in triple-negative BC (TNBC) was influenced by medications from class H, N, and A, while TIL density in HER2+ BC was associated with the use of class C. Psycholeptics (N05) and agents acting on the renin-angiotensin system (C09) were independently associated with pCR in the whole population of BC or TNBC, and in HER2-positive BC, respectively. Importantly, level 3 hypnotics (N05C) alone were able to reduce tumor growth in BC bearing mice and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner. These findings prompt for further exploration of drugs interactions in cancer, and for prospective drug-repositioning strategies to improve the efficacy of NAC in BC.

    更新日期:2019-11-14
  • GD2-targeted chimeric antigen receptor T cells prevent metastasis formation by elimination of breast cancer stem-like cells
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-07
    Christian M. Seitz, Sarah Schroeder, Philipp Knopf, Ann-Christin Krahl, Jana Hau, Sabine Schleicher, Manuela Martella, Leticia Quintanilla-Martinez, Manfred Kneilling, Bernd Pichler, Peter Lang, Daniel Atar, Karin Schilbach, Rupert Handgretinger, Patrick Schlegel

    ABSTRACT Expression of the disialoganglioside GD2 has been identified as a marker antigen associated with a breast cancer stem-like cell (BCSC) phenotype. Here, we report on the evaluation of GD2 as a BCSC-specific target antigen for immunotherapy. GD2 expression was confirmed at variable degree in a set of breast cancer cell lines, predominantly in triple-negative breast cancer (TNBC). To target GD2, we have generated novel anti-GD2 chimeric antigen receptors (GD2-CAR), based on single-chain variable fragments (scFv) derived from the monoclonal antibody (mAb) ch14.18, also known as dinutuximab beta. Expressed on T cells, GD2-CARs mediated specific GD2-dependent T-cell activation and target cell lysis. In contrast to previously described GD2-CARs, no signs of exhaustion by tonic signaling were found. Importantly, application of GD2-CAR expressing T cells (GD2-CAR-T) in an orthotopic xenograft model of TNBC (MDA-MB-231) halted local tumor progression and completely prevented lung metastasis formation. In line with the BCSC model, GD2 expression was only found in a subpopulation (4-6%) of MDA-MB-231 cells before injection. Significant expansion of GD2-CAR-T in tumor-bearing mice as well as T-cell infiltrates in the primary tumor and the lungs were found, indicating site-specific activation of GD2-CAR-T. Our data strongly support previous findings of GD2 as a BCSC-associated antigen. GD2-targeted immunotherapies have been extensively studied in human. In conclusion, GD2-CAR-T should be considered a promising novel approach for GD2-positive breast cancer, especially to eliminate disseminated tumor cells and prevent metastasis formation.

    更新日期:2019-11-07
  • A classification based on tumor budding and immune score for patients with hepatocellular carcinoma
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-07
    Li Wei, Zhang Delin, Yuan Kefei, Wu Hong, Huang Jiwei, Zhang Yange

    ABSTRACT Background: The role of immune profiling and tumor budding in hepatocellular carcinoma (HCC) remains largely unknown. This study evaluated the association between tumor budding and lymphocytic infiltration in HCC. Meanwhile, HCC patients were stratified based on tumor budding grade and immune score. Patients and methods: A total of 423 HCC patients were divided into training (n = 212) and validation (n = 211) cohort. Tumor slides from resected HCC samples were used for tumor budding assessment. A prognosis-relevant immune score was developed based on five types of immune cells out of eleven immune markers. A classification based on tumor budding grade and immune type was established (IS-TB type). To explore the association of IS-TB type and molecular alterations of HCC, 100 HCC samples and adjacent non-tumor tissues from 100 patients were investigated by whole-exome sequencing. Results: Tumor budding was an independent adverse prognostic factor for OS and DFS in both of the training and validation cohorts (all P values <.05). The rate of high-grade tumor budding was significantly higher in HCC with immature stroma (P < .001), strong α-SMA expression (P = .005), non-steatotic tumors and non-fibrolamellar-HCC (P < .001). Additionally, tumor budding was related to both anti- and pro-tumor immune responses. Patients were classified into immune type A and immune type B according to the immune score. Based on tumor budding grade and immunotype, patients were classified into four subgroups: ISA-TBhigh (type I), ISB-TBhigh (type II), ISA-TBlow (type III) and ISB-TBlow (type IV). Patients with type III tumor had the best OS and DFS, whereas OS and DFS were the worst for cases with type II tumor. TP53 mutation was more frequent in IS-TB type I (ISATBhigh) patients, while IS-TB type IV (ISBTBlow) harbored high number of CTNNB1 mutation. Conclusion: Tumor-immune cell interactions in HCC is heterogeneous. HCC classification based on tumor budding and immune score correlates with patient survival and molecular alterations. The defined subtypes may have significance for utilizing individualized treatment in patients with HCC.

    更新日期:2019-11-07
  • Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-07
    Shaokang Ma, Jonathan Chee, Vanessa S. Fear, Catherine A. Forbes, Louis Boon, Ian M. Dick, Bruce W. S. Robinson, Jenette Creaney

    ABSTRACT Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.e. asbestos) and mimics its human counterpart (i.e. mesothelioma). We identified and screened 33 candidate neo-antigens, and found T cell responses against one candidate in tumor-bearing animals, mutant UQCRC2. Interestingly, we found a high degree of inter-animal variation in the magnitude of neo-antigen responses in otherwise identical mice. ICPB therapy with Cytotoxic T-lymphocyte-associated protein (CTLA-4) and α-glucocorticoid-induced TNFR family related gene (GITR) in doses that induced tumor regression, increased the magnitude of responses and unmasked functional T cell responses against another neo-antigen, UNC45a. Importantly, the magnitude of the pre-treatment draining lymph node (dLN) response to UNC45a closely corresponded to ICPB therapy outcomes. Surprisingly however, boosting pre-treatment UNC45a-specific T cell numbers did not improve response rates to ICPB. These observations suggest a novel biomarker approach to the clinical prediction of ICPB response and have important implications for the development of neo-antigen vaccines.

    更新日期:2019-11-07
  • The prognostic impact of immune-related adverse events during anti-PD1 treatment in melanoma and non–small-cell lung cancer: a real-life retrospective study
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-05
    R. Dupont, E. Bérard, F. Puisset, T. Comont, J.-P. Delord, R. Guimbaud, N. Meyer, J. Mazieres, L. Alric

    ABSTRACT Background: Nivolumab and pembrolizumab, two PD1 inhibitors, trigger immune-related adverse events in approximately 50% of patients. Our objective was to determine whether these immune-related adverse events are associated with patient outcomes. Patients and Methods: Retrospective cohort study, realized at the Institut Universitaire du Cancer de Toulouse, of all the patients treated with nivolumab or pembrolizumab off clinical trials. We included patients (i) diagnosed with unresectable stage III or stage IV melanoma or with recurrent stage IIIB or stage IV non-small cell lung cancer (ii) on nivolumab 3mg/kg or pembrolizumab 2mg/kg every 2 or 3 weeks respectively. Results: Of the 311 patients included (of 641 eligible subjects), 120 (38.6%) had melanoma and 191 (61.4%) had non-small cell lung cancer; 241 (77.5%) were treated with nivolumab with a median follow-up of 24 months (20–29). We observed 166 immune-related adverse events in 116 (37.3%) patients, categorized as “early” (onset before 12 weeks in melanoma and before 8 weeks in lung cancer) in 63 (54.3%) patients. Early and late adverse events were significantly associated with an increase in overall survival: adjusted hazard ratio 0.58 [0.41–0.84] (p = .003) and 0.28 [0.16–0.50] (p < .001) respectively. The overall response rate was significantly increased in patients with an immune-related adverse event (53.9% vs 12.9%, p < .001) Conclusions: This study validates the association between immune-related adverse events and anti-PD1 efficacy in real-life, especially if these events are delayed. Our results, along with further studies on the place of immunosuppressive drugs in the therapeutic strategy, could improve the management of these adverse events.

    更新日期:2019-11-06
  • TCB2, a new anti-human interleukin-2 antibody, facilitates heterodimeric IL-2 receptor signaling and improves anti-tumor immunity
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-04
    Jun-Young Lee, Eunjin Lee, Sung Wook Hong, Daeun Kim, O. Eunju, Jonathan Sprent, Sin-Hyeog Im, You Jeong Lee, Charles D. Surh

    ABSTRACT IL-2 is a pleiotropic cytokine that plays an essential role in the survival, expansion, and function of CD8 T cells, regulatory T cells (Tregs), and natural killer (NK) cells. Previous studies showed that binding IL-2 with an anti-IL-2 monoclonal antibody (mAb) with a particular specificity could block its interaction with IL-2Rα, which is mainly expressed on Tregs. This selectivity can enhance the anti-tumor effects of IL-2 by activating CD8 T and NK cells, while disfavoring Treg stimulation. Based on this, we newly developed a series of anti-human IL-2 (hIL-2) mAbs (TCB1-3) that selectively stimulate CD8 T and NK cells without overtly activating Tregs. Among them, the hIL-2/TCB2 complex (hIL-2/TCB2c) exerted the best efficacy by inducing a prodigious expansion of host memory phenotype (MP) CD8 T (60-fold) and NK cells (18-fold) with less efficient Treg proliferation (5-fold). As a result, there was an average eightfold increase in the ratio of MP CD8 to Tregs. Accordingly, hIL-2/TCB2c strongly inhibited the growth of B16F10, MC38, and CT26 tumors. More remarkably, hIL-2/TCB2c showed synergy with checkpoint inhibitors such as anti-CTLA-4 or PD1 antibodies, and resulted in almost complete regression of implanted tumors and resistance to secondary tumor challenge. For direct clinical use, we generated a humanized form of TCB2 that had equal immunostimulatory and anti-tumor efficacy as a murine one. Collectively, these results show that TCB2 can provide a potent immunotherapeutic modality either alone or together with checkpoint inhibitors in cancer patients.

    更新日期:2019-11-05
  • B7-H3 specific T cells with chimeric antigen receptor and decoy PD-1 receptors eradicate established solid human tumors in mouse models
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-04
    Baozhu Huang, Liqun Luo, Jun Wang, Bailin He, Rui Feng, Na Xian, Qiong Zhang, Lieping Chen, Gangxiong Huang

    ABSTRACT The application of chimeric antigen receptor (CAR)-T cell therapy in patients with advanced solid tumors remains a significant challenge. Simultaneously targeting antigen and the solid tumor microenvironment are two major factors that greatly impact CAR-T cell therapy outcomes. In this study, we engineered CAR-T cells to specifically target B7-H3, a protein commonly found in solid human tumors, using a single-chain variable fragment (scFv) derived from an anti-B7-H3 monoclonal antibody. We tested the antitumor activity of B7-H3 CAR-T cells in mouse models with solid human tumors and determined that B7-H3 CAR-T cells exhibited potent antitumor activity against B7-H3+ tumor cells in vitro and in vivo. In addition, PD-1 decoy receptors were engineered to include extracellular PD-1 fused to the intracellular stimulatory domain of either CD28 or IL-7 receptor, respectively, which were then introduced into B7-H3 CAR-T cells. As a result, these newly modified, superior CAR-T cells exhibited more persistent antitumor activity in B7-H3+/B7-H1+ tumors in vivo. Our findings indicate that B7-H3 specific CAR-T cells have the potential to treat multiple types of advanced solid tumors.

    更新日期:2019-11-05
  • Epstein–Barr virus-positive diffuse large B-cell lymphoma features disrupted antigen capture/presentation and hijacked T-cell suppression
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-03
    Xiang-Nan Jiang, Bao-Hua Yu, Wan-Hui Yan, Jimmy Lee, Xiao-Yan Zhou, Xiao-Qiu Li

    ABSTRACT Background: B cells can function as antigen-presenting cells by presenting antigens captured by the B-cell receptor (BCR) on Class II Major Histocompatibility Complex (MHC II) to T cells. In addition, B-cells can also maintain immune homeostasis by expressing PD-L1 and suppressing T-cell activity. Epstein-Barr virus (EBV) infection can disrupt B-cell function and lead to B cell malignancies, including diffuse large B-cell lymphoma (DLBCL). Here we show that EBV-positive DLBCL (EBV+ DLBCL) has decreased expression of BCR and MHC II, but over-expressed PD-L1, which may lead to immune evasion. Methods: An EBV+ DLBCL cohort (n = 30) and an EBV- DLBCL control cohort (n = 83) were established. Immunostaining of PD-L1, MHC II, MHC II Transactivator (CIITA) and pBTK was performed on automated stainer. H-score was used to denote the results of staining of PD-L1 and pBTK. Break apart and deletion of CIITA locus was studied by fluorescent in situ hybridization. Surface immunoglobulin mean fluorescent insensitivity (MFI) was detected by flow cytometry to demonstrate the level BCR. Results: EBV+ DLBCL showed significantly lower expression of CIITA and MHC II compared to EBV- DLBCL. Genetic aberrations involving CIITA were also more common in EBV+ DLBCL, with 23% break apart events and 6% deletion events, comparted to 2% break apart and 0% deletion in EBV- DLBCL. In addition to the loss of antigen presentation molecule, the antigen capture receptor, BCR, was also down-regulated in EBV+ DLBCL. Accordingly, BCR signaling was also significantly decreased in EBV+ DLBCL as denoted by the respective pBTK levels. Conclusions: EBV+ DLBCL shows over expression of the T-cell inhibitory ligand, PD-L1. Antigen capture and presentation system were disrupted, and T-cell inhibitory molecule was hijacked in EBV+ DLBCL, which may contribute to immune escape in this high risk disease. Therapies targeting these aberrations may improve the outcome of patients with EBV+ DLBCL.

    更新日期:2019-11-04
  • The M2 macrophage marker CD206: a novel prognostic indicator for acute myeloid leukemia
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-03
    Zi-Jun Xu, Yu Gu, Cui-Zhu Wang, Ye Jin, Xiang-Mei Wen, Ji-Chun Ma, Li-Juan Tang, Zhen-Wei Mao, Jun Qian, Jiang Lin

    ABSTRACT Hematological malignancies possess a distinctive immunologic microenvironment compared with solid tumors. Here, using an established computational algorithm (CIBERSORT), we systematically analyzed the overall distribution of 22 tumor-infiltrating leukocyte (TIL) populations in more than 2000 bone marrow (BM) samples from 5 major hematological malignancies and healthy controls. Focusing on significantly altered TILs in acute myeloid leukemia (AML), we found that patients with AML exhibited increased frequencies of M2 macrophages, compared to either healthy controls or the other four malignancies. High infiltration of M2 macrophages was associated with poor outcome in AML. Further analysis revealed that CD206, a M2 marker gene, could faithfully reflect variation in M2 fractions and was more highly expressed in AML than normal controls. High CD206 expression predicted inferior overall survival (OS) and event-free survival (EFS) in two independent AML cohorts. Among 175 patients with intermediate-risk cytogenetics, the survival still differed greatly between low and high CD206 expressers (OS; P < .0001; 3-year rates, 56% v 32%; EFS; P < .001; 3-year rates, 47% v 25%). When analyzed in a meta-analysis, CD206 as a continuous variable showed superior predictive performance than classical prognosticators in AML (BAALC, ERG, EVI1, MN1, and WT1). In summary, M2 macrophages are preferentially enriched in AML. The M2 marker CD206 may serve as a new prognostic marker in AML.

    更新日期:2019-11-04
  • Isolated limb perfusion with melphalan activates interferon-stimulated genes to induce tumor regression in patients with melanoma in-transit metastasis
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-03
    Junko Johansson, Roberta Kiffin, Ebru Aydin, Malin S. Nilsson, Kristoffer Hellstrand, Per Lindnér, Peter Naredi, Roger Olofsson Bagge, Anna Martner

    ABSTRACT Hyperthermic isolated limb perfusion (ILP) with high-dose melphalan is a treatment option for melanoma patients with metastasis confined to limbs (in-transit metastasis). The therapy entails a complete response (CR) rate of 50–70%. Cellular immunity is proposed to impact on the clinical efficacy of ILP, but the detailed aspects of ILP-induced immune activation remain to be explored. For this study, we explored the potential role of interferon-stimulated gene (ISG) products, including CXCL10, CCL2, PD-L2 and IFN-γ along with expression of their cognate receptors CXCR3, CCR4, CCR5 and PD-1 on lymphocytes, for the clinical efficacy of ILP. Patients with high serum levels of CXCL10, CCL2, PD-L2 and IFN-γ were more likely to achieve CR after ILP. Additionally, the expression of CXCR3, CCR4 and CCR5 on T cells and/or natural killer (NK) cells was enhanced by ILP. Peripheral blood mononuclear cells (PBMCs) secreted high levels of CXCL10, CCL2 and IFN-γ in response to co-culture with melphalan-exposed melanoma cells in vitro. Activated T cells migrated toward supernatants from these co-cultures. Furthermore, melphalan-exposed melanoma cells triggered upregulation of CXCR3, CCR4, CCR5 and PD-1 on co-cultured T cells and/or NK cells. Our results suggest that constituents released from melphalan-exposed melanoma cells stimulate the ISG axis with ensuing formation of chemokines and upregulation of chemokine receptor expression on anti-neoplastic immune cells, which may contribute in ILP-induced tumor regression.

    更新日期:2019-11-04
  • Identification of a CD8+ T-cell response to a predicted neoantigen in malignant mesothelioma
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-03
    Sophie Sneddon, Craig M. Rive, Shaokang Ma, Ian M. Dick, Richard J. N. Allcock, Scott D. Brown, Robert A. Holt, Mark Watson, Shay Leary, Y. C. Gary Lee, Bruce W. S. Robinson, Jenette Creaney

    ABSTRACT Neoantigens present unique and specific targets for personalized cancer immunotherapy strategies. Given the low mutational burden yet immunotherapy responsiveness of malignant mesothelioma (MM) when compared to other carcinogen-induced malignancies, identifying candidate neoantigens and T cells that recognize them has been a challenge. We used pleural effusions to gain access to MM tumor cells as well as immune cells in order to characterize the tumor-immune interface in MM. We characterized the landscape of potential neoantigens from SNVs identified in 27 MM patients and performed whole transcriptome sequencing of cell populations from 18 patient-matched pleural effusions. IFNγ ELISpot was performed to detect a CD8+ T cell responses to predicted neoantigens in one patient. We detected a median of 68 (range 7–258) predicted neoantigens across the samples. Wild-type non-binding to mutant binding predicted neoantigens increased risk of death in a model adjusting for age, sex, smoking status, histology and treatment (HR: 33.22, CI: 2.55–433.02, p = .007). Gene expression analysis indicated a dynamic immune environment within the pleural effusions. TCR clonotypes increased with predicted neoantigen burden. A strong activated CD8+ T-cell response was identified for a predicted neoantigen produced by a spontaneous mutation in the ROBO3 gene. Despite the challenges associated with the identification of bonafide neoantigens, there is growing evidence that these molecular changes can provide an actionable target for personalized therapeutics in difficult to treat cancers. Our findings support the existence of candidate neoantigens in MM despite the low mutation burden of the tumor, and may present improved treatment opportunities for patients.

    更新日期:2019-11-04
  • Destroy, what destroys you
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-03
    Khang Luu, Emily Nickles, Herbert Schwarz

    ABSTRACT New evidence indicates the importance of CD137 for controlling Epstein-Barr virus (EBV) infections. (1) Mutations in CD137 predispose to EBV-associated diseases. (2) EBV induces ectopic CD137 expression, thereby activating a negative feed-back regulation and reducing T cell costimulation. These findings suggest CD137 agonists as new treatments for EBV-associated diseases.

    更新日期:2019-11-04
  • Targeting ST2 expressing activated regulatory T cells in Kras-mutant lung cancer
    Oncoimmunology (IF 5.333) Pub Date : 2019-11-02
    Byung-Seok Kim, Jelita Clinton, Qing Wang, Seon Hee Chang

    ABSTRACT Oncogenic KRAS-mutant lung cancers remain treatment refractory. A better understanding of the immune response of KRAS-mutant lung cancers is required to facilitate the development of potential therapeutic strategies. Regulatory T cells (Tregs) are a subset of immune cells that promote tumor progression through suppressing anti-tumor immune response. Here, we used KrasG12D lung cancer mice to examine the characteristics of tumor-infiltrating Tregs. In tumor-bearing animals, Tregs are increased during tumor progression. Of note, a majority of Tregs that localized in lung tumors of Kras-mutant mice expressed ST2, a receptor for IL-33, which are different from Tregs in secondary lymphoid organs. To investigate the function of local Tregs influencing immune response in primary lung tumor development, we used anti-ST2 antibody to deplete Tregs in lung tumors of Kras-mutant mice. Treatment of Kras-mutant mice with anti-ST2 antibody resulted in depletion of activated Tregs in lung tumor while leaving Tregs in secondary lymphoid organs intact. Also, localized Tregs depletion led to a significant reduction in lung tumor burden. Immune response after Tregs depletion in tumors showed restoration of NK cell activity and enhanced Th1 activity, with increased CD8 cytotoxic T cell response. In addition, we found that the M2 macrophage signature in lung tumors was suppressed upon Tregs depletion, accompanied by upregulation of surface expression of MHC-II molecules and reduced expression of Arg1, Mmp12, Cxcl2, and Chi3l3. These data suggest that therapeutic strategies targeting activated Tregs in lung cancer have the potential to restrain tumor progression by enhancing anti-tumor immunity.

    更新日期:2019-11-04
  • IFNβ-producing CX3CR1+ macrophages promote T-regulatory cell expansion and tumor growth in the APCmin/+ / Bacteroides fragilis colon cancer model
    Oncoimmunology (IF 5.333) Pub Date : 2019-09-28
    Tao Gu, Qingsheng Li, Nejat K. Egilmez

    ABSTRACT Increased T-regulatory cell activity drives tumor progression in the compound APCmin/+/enterotoxic Bacteroides fragilis colon cancer model. At the same time, how microbially-induced inflammation promotes T-regulatory cell expansion in the dysplastic intestine remains poorly described. Analysis of post-infection immune cell kinetics in the colon lamina propria revealed that CD4+ Foxp3+ cell numbers increased by 25-fold between days 3–14. Importantly, T-regulatory cell expansion was preceded by a 12-fold spike in lamina propria CD11b+ cell numbers between days 0–4; suggesting a link between the myeloid compartment and the T-regulatory cells. Consistent with this notion, in vitro co-culture studies utilizing sorted myeloid cell subsets and CD4+ T-cells demonstrated that the CD11b+CX3CR1+ but not the CD11b+CX3CR1− subset preferentially induced Foxp3 expression in CD4+ T-cells. Phenotypic analysis revealed that the CD11b+CX3CR1+ subset represented a homogenous CD64+CD24−CD103a− macrophage population. Global CX3CR1 knockout or conditional depletion of CX3CR1+ myeloid cells resulted in diminished CD4+Foxp3+ cell expansion and a 3 to 6-fold reduction in tumor burden establishing CX3CR1+ macrophages as a major driver of the T-regulatory cell-tumor axis. Quantitative analysis of CD11b+ myeloid cell subsets for IFNβ mRNA revealed that the CX3CR1+ macrophages expressed 15-fold higher levels of IFNβ in comparison to the CX3CR1− myeloid subset. Antibody mediated neutralization of IFNβ resulted in the suppression of CD4+Foxp3+ cell induction and tumor growth, demonstrating the central role of IFNβ in mediating CX3CR1+ macrophage-driven T-regulatory cell expansion. These studies shed new mechanistic light on the cellular ontogeny of pro-tumorigenic T-regulatory cells in the inflamed colon of the APCmin/+ mouse.

    更新日期:2019-11-04
  • Langerhans cells and NK cells cooperate in the inhibition of chemical skin carcinogenesis.
    Oncoimmunology (IF 5.333) Pub Date : 2017-03-28
    Daniela Ortner,Christoph H Tripp,Kerstin Komenda,Sandrine Dubrac,Bernhard Zelger,Martin Hermann,Wolfgang Doppler,Piotr Z Tymoszuk,Louis Boon,Björn E Clausen,Patrizia Stoitzner

    Tissue immunosurveillance is an important mechanism to prevent cancer. Skin treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), followed by the tumor promoter 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), is an established murine model for squamous cell carcinoma (SCC). However, the innate immunological events occurring during the initiation of chemical carcinogenesis with DMBA remain elusive. Here, we discovered that natural killer (NK) cells and Langerhans cells (LC) cooperate to impair this oncogenic process in murine skin. The depletion of NK cells or LC caused an accumulation of DNA-damaged, natural killer group 2D-ligand (NKG2D-L) expressing keratinocytes and accelerated tumor growth. Notably, the secretion of TNFα mainly by LC promoted the recruitment of NK cells into the epidermis. Indeed, the TNFα-induced chemokines CCL2 and CXCL10 directed NK cells to DMBA-treated epidermis. Our findings reveal a novel mechanism how innate immune cells cooperate in the inhibition of cutaneous chemical carcinogenesis.

    更新日期:2019-11-01
  • CIITA-related block of HLA class II expression, upregulation of HLA class I, and heterogeneous expression of immune checkpoints in hepatocarcinomas: implications for new therapeutic approaches.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-07
    Elise Ramia,Anna Maria Chiaravalli,Farah Bou Nasser Eddine,Alessandra Tedeschi,Fausto Sessa,Roberto S Accolla,Greta Forlani

    Hepatocellular carcinoma (HCC) is the second cause of death for cancer worldwide, justifying the urgent need for novel therapeutic approaches. Immunotherapeutic strategies based on triggering and/or rescuing tumor antigen-specific T cells may be promising particularly if combined together. As preliminary step toward this goal, we have investigated the expression of antigen presenting molecules (HLA class I and class II) and immune checkpoints (PD-1 and PD-L1) in 43 HCC samples from distinct patients and in HCC cell lines. While normal hepatocytes did not express HLA class I and II, HCC cells strongly upregulated HLA class I while remaining negative for HLA class II. The absence of HLA class II expression in HCC cell lines correlated with lack of expression of the HLA class II transactivator, CIITA, which could not be rescued even after interferon-gamma treatment. This was due to high methylation levels of interferon-gamma-sensitive CIITA promoter IV strongly suggesting a biologically relevant developmental silencing of HLA-II expression in liver cell lineage. HCC tumor tissues showed a variable degree of leukocyte infiltration. Infiltrating lymphocytes expressed PD-1, while PD-L1 was expressed in cells with monocyte-macrophage morphology mostly localized at the tumor margin, but not in tumor cells. De novo expression of HLA class I, instrumental for presenting tumor antigens to cytotoxic T lymphocytes, and the correct characterization of the cells expressing checkpoint inhibitors in the tumor tissue should be the ground for setting novel strategies of combined approaches of immunotherapy in HCC based on tumor peptide vaccines and anti-checkpoint inhibitor antibodies.

    更新日期:2019-11-01
  • The novel agonistic iNKT-cell antibody NKT14m induces a therapeutic antitumor response against B-cell lymphoma.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Laura Escribà-Garcia,Carmen Alvarez-Fernández,Ana Carolina Caballero,Robert Schaub,Jorge Sierra,Javier Briones

    Invariant natural killer T (iNKT) cells are a small population of T lymphocytes that expresses an invariant T cell receptor with a unique specificity for glycolipid antigens. Their activation using the glycolipid α-galactosylceramide (α-GalCer) triggers innate and adaptive immune responses. The use of α-GalCer in preclinical models as a single antitumor treatment showed moderate effect, but its efficacy in cancer patients was less effective. In addition, this glycolipid induces long-term iNKT-cell anergy precluding the possibility of retreatment. Recently, the first murine iNKT-cell agonistic antibody, NKT14m, has been developed. Here, we analyzed, for the first time, the antitumor efficacy of NKT14m in a B-cell lymphoma model. In a therapeutic setting, a single dose of NKT14m had a moderate antitumor efficacy that was associated with an increase of IFN-γ producing iNKT cells even after a second dose of the NKT14m antibody. Importantly, the combination of a single dose of NKT14m with cyclophosphamide had a potent antitumor efficacy and long-lasting immunity in vivo. Our findings provide the first evidence of the in vivo antitumor efficacy of NKT14m antibody, showing that, either alone or in combination with chemotherapy, induces an effective antitumor response. These results open new opportunities for iNKT-cell mediated immunotherapy to treat B-cell lymphoma.

    更新日期:2019-11-01
  • Discovering cancer immunotherapy targets in vivo.
    Oncoimmunology (IF 5.333) Pub Date : 2014-07-23
    Penghui Zhou,Kai W Wucherpfennig

    A key challenge facing the cancer immunology field is the discovery of the most suitable targets for therapeutic intervention. We recently reported a novel RNA-interference (RNAi)-based approach for systematic discovery of such targets in the tumor microenvironment in vivo utilizing pooled shRNA libraries as a screening tool. Here, we discuss applying this unbiased method to develop innovative cancer therapeutics.

    更新日期:2019-11-01
  • Batf3+ DCs and type I IFN are critical for the efficacy of neoadjuvant cancer immunotherapy.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Jing Liu,Elisa A Rozeman,Jake S O'Donnell,Stacey Allen,Lorenzo Fanchi,Mark J Smyth,Christian U Blank,Michele W L Teng

    New clinical trials are now evaluating the efficacy of neoadjuvant immunotherapy in the context of primary tumor surgery. Using the orthotopic 4T1.2 mouse model of spontaneously metastatic mammary cancer, we have shown that neoadjuvant immunotherapy and surgery was superior in the generation of tumor-specific CD8+ T cells and eradication of lethal metastases compared to surgery followed by adjuvant immunotherapy. However, the importance of host Batf3 and type I interferon (IFN) for long-term survival of mice following neoadjuvant immunotherapy is unknown. Here we demonstrated that loss of Batf3+ DCs or type I IFN receptor blockade in 4T1.2 tumor-bearing mice treated with neoadjuvant anti-PD-1+anti-CD137 immunotherapy reduced long-term survival with a corresponding reduction in tumor-specific CD8+ T cells producing effector cytokines in the primary tumor and in the periphery. Interestingly, we found all high-risk stage III melanoma patients relapsing after adjuvant or neoadjuvant ipilimumab+nivolumab within the OpACIN trial (NCT02437279) displayed low expression of Batf3+ DC-associated genes in pre-treatment tumor biopsies. Further focus should now be placed on validating the requirement of an intratumoral Batf3+ DC gene signature for response to neoadjuvant immunotherapy.

    更新日期:2019-11-01
  • Formation and phenotypic characterization of CD49a, CD49b and CD103 expressing CD8 T cell populations in human metastatic melanoma.
    Oncoimmunology (IF 5.333) Pub Date : 2018-10-06
    Marit M Melssen,Walter Olson,Nolan A Wages,Brian J Capaldo,Ileana S Mauldin,Adela Mahmutovic,Ciara Hutchison,Cornelis J M Melief,Timothy N Bullock,Victor H Engelhard,Craig L Slingluff

    Integrins α1β1 (CD49a), α2β1 (CD49b) and αEβ7 (CD103) mediate retention of lymphocytes in peripheral tissues, and their expression is upregulated on tumor infiltrating lymphocytes (TIL) compared to circulating lymphocytes. Little is known about what induces expression of these retention integrins (RI) nor whether RI define subsets in the tumor microenvironment (TME) with a specific phenotype. Human metastatic melanoma-derived CD8 TIL could be grouped into five subpopulations based on RI expression patterns: RIneg, CD49a+ only, CD49a+CD49b+, CD49a+CD103+, or positive for all three RI. A significantly larger fraction of the CD49a+ only subpopulation expressed multiple effector cytokines, whereas CD49a+CD103+ and CD49a+CD49b+ cells expressed IFNγ only. RIneg and CD49a+CD49b+CD103+ CD8 TIL subsets expressed significantly less effector cytokines overall. Interestingly, however, CD49a+CD49b+CD103+ CD8 expressed lowest CD127, and highest levels of perforin and exhaustion markers PD-1 and Tim3, suggesting selective exhaustion rather than conversion to memory. To gain insight into RI expression induction, normal donor PBMC were cultured with T cell receptor (TCR) stimulation and/or cytokines. TCR stimulation alone induced two RI+ cell populations: CD49a single positive and CD49a+CD49b+ cells. TNFα and IL-2 each were capable of inducing these populations. Addition of TGFβ to TCR stimulation generated two additional populations; CD49a+CD49bnegCD103+ and CD49a+CD49b+CD103+. Taken together, our findings identify opportunities to modulate RI expression in the TME by cytokine therapies and to generate subsets with a specific RI repertoire in the interest of augmenting immune therapies for cancer or for modulating other immune-related diseases such as autoimmune diseases.

    更新日期:2019-11-01
  • Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Daniel Newsted,Sunandan Banerjee,Kathleen Watt,Sarah Nersesian,Peter Truesdell,Levi L Blazer,Lia Cardarelli,Jarrett J Adams,Sachdev S Sidhu,Andrew W Craig

    Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. EOC is often diagnosed at late stages, with peritoneal metastases and ascites production. Current surgery and platinum-based chemotherapy regimes fail to prevent recurrence in most patients. High levels of Transforming growth factor-β (TGF-β) within ascites has been linked to poor prognosis. TGF-β signaling promotes epithelial-mesenchymal transition (EMT) in EOC tumor cells, and immune suppression within the tumor microenvironment, with both contributing to chemotherapy resistance and metastasis. The goal of this study was to develop specific synthetic inhibitory antibodies to the Type II TGF-β receptor (TGFBR2), and test these antibodies in EOC cell and tumor models. Following screening of a phage-displayed synthetic antigen-binding fragment (Fab) library with the extracellular domain of TGFBR2, we identified a lead inhibitory Fab that suppressed TGF-β signaling in mouse and human EOC cell lines. Affinity maturation of the lead inhibitory Fab resulted in several derivative Fabs with increased affinity for TGFBR2 and efficacy as suppressors of TGF-β signaling, EMT and EOC cell invasion. In EOC xenograft and syngeneic tumor models, blockade of TGFBR2 with our lead antibodies led to improved chemotherapy response. This correlated with reversal of EMT and immune exclusion in these tumor models with TGFBR2 blockade. Together, these results describe new inhibitors of the TGF-β pathway that improve antitumor immunity, and response to chemotherapy in preclinical EOC models.

    更新日期:2019-11-01
  • Chronic inflammation in endometriosis and endometriosis-associated ovarian cancer: New roles for the "old" complement pathway.
    Oncoimmunology (IF 5.333) Pub Date : 2015-07-15
    Robert P Edwards,Xin Huang,Anda M Vlad

    Immune escape is consequential for cancer development. Identifying abnormalities of the immune microenvironment during early carcinogenesis can provide insight into disease pathogenesis and unravel new preventive or therapeutic targets. We recently conducted a comprehensive immune gene expression analysis in endometriosis and endometriosis-associated ovarian cancer and explored new mechanistic roles for the complement pathway.

    更新日期:2019-11-01
  • Human Mesenchymal glioblastomas are characterized by an increased immune cell presence compared to Proneural and Classical tumors.
    Oncoimmunology (IF 5.333) Pub Date : 2019-10-28
    Ioannis Kaffes,Frank Szulzewsky,Zhihong Chen,Cameron J Herting,Ben Gabanic,José E Velázquez Vega,Jennifer Shelton,Jeffrey M Switchenko,James L Ross,Leon F McSwain,Jason T Huse,Bengt Westermark,Sven Nelander,Karin Forsberg-Nilsson,Lene Uhrbom,Naga Prathyusha Maturi,Patrick J Cimino,Eric C Holland,Helmut Kettenmann,Cameron W Brennan,Daniel J Brat,Dolores Hambardzumyan

    Glioblastoma (GBM) is the most aggressive malignant primary brain tumor in adults, with a median survival of 14.6 months. Recent efforts have focused on identifying clinically relevant subgroups to improve our understanding of pathogenetic mechanisms and patient stratification. Concurrently, the role of immune cells in the tumor microenvironment has received increasing attention, especially T cells and tumor-associated macrophages (TAM). The latter are a mixed population of activated brain-resident microglia and infiltrating monocytes/monocyte-derived macrophages, both of which express ionized calcium-binding adapter molecule 1 (IBA1). This study investigated differences in immune cell subpopulations among distinct transcriptional subtypes of GBM. Human GBM samples were molecularly characterized and assigned to Proneural, Mesenchymal or Classical subtypes as defined by NanoString nCounter Technology. Subsequently, we performed and analyzed automated immunohistochemical stainings for TAM as well as specific T cell populations. The Mesenchymal subtype of GBM showed the highest presence of TAM, CD8+, CD3+ and FOXP3+ T cells, as compared to Proneural and Classical subtypes. High expression levels of the TAM-related gene AIF1, which encodes the TAM-specific protein IBA1, correlated with a worse prognosis in Proneural GBM, but conferred a survival benefit in Mesenchymal tumors. We used our data to construct a mathematical model that could reliably identify Mesenchymal GBM with high sensitivity using a combination of the aforementioned cell-specific IHC markers. In conclusion, we demonstrated that molecularly distinct GBM subtypes are characterized by profound differences in the composition of their immune microenvironment, which could potentially help to identify tumors amenable to immunotherapy.

    更新日期:2019-11-01
  • Beneficial effects of sunitinib on tumor microenvironment and immunotherapy targeting death receptor5.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Yoko Tsukita,Tatsuma Okazaki,Satoru Ebihara,Riyo Komatsu,Mayumi Nihei,Makoto Kobayashi,Taizou Hirano,Hisatoshi Sugiura,Tsutomu Tamada,Nobuyuki Tanaka,Yasufumi Sato,Hideo Yagita,Masakazu Ichinose

    Tumor-associated blood vessels and lymphatics are abnormal and dysfunctional. These are hallmarks of the tumor microenvironment, which has an immunosuppressive nature, such as through hypoxia. Treatment with anti-death receptor5 (DR5) monoclonal antibody MD5-1, which induces tumor cell death, is a potent anti-tumor immunotherapy. Generally, MD5-1 induces cell death mainly via antigen presenting cells (APCs) and generates tumor-specific effector T cells. To date, the effects of a simultaneous functional improvement of abnormal blood vessels and lymphatics on the immune microenvironment are largely unknown. A combination therapy using sunitinib, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor inhibitor, and MD5-1 substantially inhibited tumor growth. Sunitinib improved pericyte coverage on endothelial cells and the expression levels of regulator of G-protein signaling 5, suggesting blood vessel normalization. Sunitinib also increased lymph flow from tumors to central lymph nodes, suggesting improved lymphatic function. In concordance with improved vasculature functions, sunitinib alleviated the tumor hypoxia, suggesting an improved tumor microenvironment. Indeed, the combination therapy induced strong activation of CD8+ T cells and dendritic cells in draining lymph nodes. The combination therapy reduced the ratio of immune-suppressive T regulatory cells in the tumors and draining lymph nodes. The combination therapy enhanced the numbers and activation of tumor-infiltrating CD8+ T cells. CD4 and/or CD8 depletion, or APC inhibiting experiments showed the contribution of CD8+ T cells and APCs to the combination therapy. These findings suggest that targeting blood vessels and lymphatics may have potential benefits for immunotherapy mediated by CD8+ T cells and APCs.

    更新日期:2019-11-01
  • Daratumumab induces CD38 internalization and impairs myeloma cell adhesion.
    Oncoimmunology (IF 5.333) Pub Date : 2018-10-06
    Jayeeta Ghose,Domenico Viola,Cesar Terrazas,Enrico Caserta,Estelle Troadec,Jihane Khalife,Emine Gulsen Gunes,James Sanchez,Tinisha McDonald,Guido Marcucci,Balveen Kaur,Michael Rosenzweig,Jonathan Keats,Steven Rosen,Amrita Krishnan,Abhay R Satoskar,Craig C Hofmeister,Flavia Pichiorri

    Daratumumab (Dara), a human immunoglobulin G1 kappa (IgG1κ) monoclonal anti-CD38 antibody, has been approved by the U.S. Food and Drug Administration for the treatment of relapsed multiple myeloma (MM) as a single agent as well as in combination with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI). Although the scientific rationale behind the use of Dara in combination with IMiDs has been extensively explored, the molecular mechanisms underlying Dara-PI regimens have not yet been investigated. Here, we demonstrate that CD38 on the surface of MM cells is rapidly internalized after Dara treatment; we also show that Dara treatment impairs MM cell adhesion, an effect that can be rescued by using the endocytosis inhibitor Dynasore. Finally, we show that Dara potentiates bortezomib (BTZ) killing of MM cells in vitro and in vivo, independent of its function as an immune activator. In conclusion, our data show that Dara impairs MM cell adhesion, which results in an increased sensitivity of MM to proteasome inhibition.

    更新日期:2019-11-01
  • Schweinfurthin natural products induce regression of murine melanoma and pair with anti-PD-1 therapy to facilitate durable tumor immunity.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Kathleen M Kokolus,Jeremy S Haley,Emily J Koubek,Raghavendra Gowda,Saketh S Dinavahi,Arati Sharma,David F Claxton,Klaus F Helm,Joseph J Drabick,Gavin P Robertson,Jeffrey D Neighbors,Raymond J Hohl,Todd D Schell

    Metastatic melanoma is a significant clinical problem with a 5-year survival rate of only 15-20%. Recent approval of new immunotherapies and targeted inhibitors have provided much needed options for these patients, in some cases promoting dramatic disease regressions. In particular, antibody-based therapies that block the PD-1/PD-L1 checkpoint inhibitory pathway have achieved an increased overall response rate in metastatic melanoma, yet durable response rates are reported only around 15%. To improve the overall and durable response rates for advanced-stage melanoma, combined targeted and immune-based therapies are under investigation. Here, we investigated how the natural products called schweinfurthins, which have selective anti-proliferative activity against many cancer types, impact anti-(α)PD-1-mediated immunotherapy of murine melanomas. Two different compounds efficiently reduced the growth of human and murine melanoma cells in vitro and induced plasma membrane surface localization of the ER-resident protein calreticulin in B16.F10 melanoma cells, an indicator of immunogenic cell death. In addition, both compounds improved αPD-1-mediated immunotherapy of established tumors in immunocompetent C57BL/6 mice either by delaying tumor progression or resulting in complete tumor regression. Improved immunotherapy was accomplished following only a 5-day course of schweinfurthin, which was associated with initial tumor regression even in the absence of αPD-1. Schweinfurthin-induced tumor regression required an intact immune system as tumors were unaffected in NOD scid gamma (NSG) mice. These results indicate that schweinfurthins improve αPD-1 therapy, leading to enhanced and durable anti-tumor immunity and support the translation of this novel approach to further improve response rates for metastatic melanoma.

    更新日期:2019-11-01
  • DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Asma A Elashi,Varun Sasidharan Nair,Rowaida Z Taha,Hibah Shaath,Eyad Elkord

    Aberrant expression of immune checkpoints (ICs) in cancer creates an immunosuppressive microenvironment, which supports immune evasion of tumor cells. We have recently reported that epigenetic modifications are critical for ICs expression in the tumor microenvironment (TME) of primary breast cancer (PBC) and colorectal cancer (CRC). Herein, we investigated transcriptomic expression of ICs (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT) and PD-L1 in peripheral blood of PBC and CRC patients, compared to healthy donors (HD). We found that expressions of TIM-3, TIGIT, PD-L1 were significantly upregulated, while LAG-3 expression was downregulated in peripheral blood of PBC and CRC patients. Demethylation enzymes TET2 and TET3 were also upregulated. In addition, promoter DNA methylation status of PD-1 was significantly hypermethylated, while PD-L1 was hypomethylated in PBC and CRC patients. Furthermore, TIGIT was significantly hypomethylated only in CRC patients. Remarkably, promoter methylation status of LAG-3, TIGIT and PD-L1 was in concordance with transcriptomic expression in CRC: the more the hypomethylation, the higher the expression. In comparison, we found that CTLA-4, TIM-3, TIGIT and PD-L1 in PBC, and CTLA-4 in CRC patients were significantly upregulated in peripheral blood, compared with tumor tissues of the same patients. However, demethylation status of all ICs was higher in TT, except for TIGIT in PBC, and CTLA-4 in CRC patients. These data indicate that the underlying mechanisms behind peripheral upregulation of PD-L1 and TIGIT in cancer patients could be due to aberrant promoter methylation profile. Moreover, demethylation inhibitors together with anti-PD-L1/anti-TIGIT could be a more efficient therapeutic strategy in cancer patients.

    更新日期:2019-11-01
  • Pre-clinical development of Listeria-based nanovaccines as immunotherapies for solid tumours: insights from melanoma.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Hector Terán-Navarro,Ricardo Calderon-Gonzalez,David Salcines-Cuevas,Isabel García,Marco Marradi,Javier Freire,Erwan Salmon,Mar Portillo-Gonzalez,Elisabet Frande-Cabanes,Almudena García-Castaño,Virginia Martinez-Callejo,Javier Gomez-Roman,Raquel Tobes,Fernando Rivera,Sonsoles Yañez-Diaz,Carmen Álvarez-Domínguez

    Gold glyconanoparticles loaded with the listeriolysin O peptide 91-99 (GNP-LLO91-99), a bacterial peptide with anti-metastatic properties, are vaccine delivery platforms facilitating immune cell targeting and increasing antigen loading. Here, we present proof of concept analyses for the consideration of GNP-LLO91-99 nanovaccines as a novel immunotherapy for cutaneous melanoma. Studies using mouse models of subcutaneous melanoma indicated that GNP-LLO91-99 nanovaccines recruite and modulate dendritic cell (DC) function within the tumour, alter tumour immunotolerance inducing melanoma-specific cytotoxic T cells, cause complete remission and improve survival. GNP-LLO91-99 nanovaccines showed superior tumour regression and survival benefits, when combined with anti-PD-1 or anti-CTLA-4 checkpoint inhibitors, resulting in an improvement in the efficacy of these immunotherapies. Studies on monocyte-derived DCs from patients with stage IA, IB or IIIB melanoma confirmed the ability of GNP-LLO91-99 nanovaccines to complement the action of checkpoint inhibitors, by not only reducing the expression of cell-death markers on DCs, but also potentiating DC antigen-presentation. We propose that GNP-LLO91-99 nanovaccines function as immune stimulators and immune effectors and serve as safe cancer therapies, alone or in combination with other immunotherapies.

    更新日期:2019-11-01
  • Genomic and transcriptional Profiling of tumor infiltrated CD8+ T cells revealed functional heterogeneity of antitumor immunity in hepatocellular carcinoma.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Zhenli Li,Geng Chen,Zhixiong Cai,Xiuqing Dong,Liman Qiu,Haipo Xu,Yongyi Zeng,Xiaolong Liu,Jingfeng Liu

    As key players in HCC antitumor response, the functions of tumor infiltrated CD8+ T cells are significantly affected by surrounding microenvironment. A detailed profiling of their genomic and transcriptional changes could provide valuable insights for both future immunotherapy development and prognosis evaluation. We performed whole exome and transcriptome sequencing on tumor infiltrated CD8+ T cells and CD8+ T cells isolated from other tissue origins (peritumor tissues and corresponding PBMCs) in eight treatment-naive HCC patients. The results demonstrated that transcriptional changes, rather than genomic alterations were the main contributors to the functional alterations of CD8+ T cells in the process of tumor progression. The origins of CD8+ T cells defined their transcriptional landscape, while the tumor infiltrated CD8+ T cells shared more similarity with peritumor-derived CD8+ T cells compared with those CD8+ T cells in blood. In addition, tumor infiltrated CD8+ T cells also showed larger transcriptional heterogeneity among individuals, which was modulated by clinical features such as HBV levels, preoperative anti-viral treatment and the degree of T cell infiltration. We also identified multiple inter-connected pathways involved in the activation and exhaustion of tumor infiltrated CD8+ T cells, among which IL-12 mediated pathway could dynamically reflect the functional status of CD8+ TILs and activation of this pathway indicated a better prognosis. Our results presented an overview picture of CD8+ TILs' genomic and transcriptional landscape and features, as well as how the functional status of CD8+ TILs correlated with patients' clinical course.

    更新日期:2019-11-01
  • NF-κB RelA renders tumor-associated macrophages resistant to and capable of directly suppressing CD8+ T cells for tumor promotion.
    Oncoimmunology (IF 5.333) Pub Date : 2018-06-07
    Liwen Li,Lei Han,Fan Sun,Jingjiao Zhou,Kim C Ohaegbulam,Xudong Tang,Xingxing Zang,Kris A Steinbrecher,Zhaoxia Qu,Gutian Xiao

    Activation of the inflammatory transcription factor NF-κB in tumor-associated macrophages (TAMs) is assumed to contribute to tumor promotion. However, whether and how NF-κB drives the antitumor macrophages to become pro-tumorigenic have not been determined in any cancer type yet. Similarly, how TAMs repress CD8+ cytotoxic T lymphocytes (CTLs) remains largely unknown, although their importance in regulatory T (Treg) cell regulation and tumor promotion has been well appreciated. Here, using an endogenous lung cancer model we uncover a direct crosstalk between TAMs and CTLs. TAMs suppress CTLs through the T-cell inhibitory molecule B7x (B7-H4/B7S1) in a cell-cell contact manner, whereas CTLs kill TAMs in a tumor antigen-specific manner. Remarkably, TAMs secrete the known T-cell suppressive cytokine interleukin-10 (IL-10) to activate, but not to repress, CTLs. Notably, one major role of cell-intrinsic NF-κB RelA is to drive TAMs to suppress CTLs for tumor promotion. It induces B7x expression in TAMs directly, and restricts IL-10 expression indirectly by repressing expression of the NF-κB cofactor Bcl3 and subsequent Bcl3/NF-κB1-mediated transcription of IL-10. It also renders TAMs resistant to CTLs by up-regulating anti-apoptotic genes. These studies help understand how immunity is shaped in lung tumorigenesis, and suggest a RelA-targeted immunotherapy for this deadliest cancer.

    更新日期:2019-11-01
  • CD28H expression identifies resident memory CD8 + T cells with less cytotoxicity in human peripheral tissues and cancers.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Yu Tian,Yi Sun,Fan Gao,Michelle R Koenig,Alexander Sunderland,Yuki Fujiwara,Robert J Torphy,Lieping Chen,Barish H Edil,Richard D Schulick,Yuwen Zhu

    The CD28H/B7-H5 pathway is a newly identified pathway of the B7 family. In human peripheral blood, the receptor CD28H is preferentially expressed on naïve T cells and repetitive stimulation of T cells leads to the loss of CD28H expression. Here we examined the expression of the CD28H/B7-H5 pathway in human peripheral tissues, as well as in human cancers. We found that CD28H is preferentially expressed on T cells with tissue-resident phenotypes (TRM). Supporting that, stimulation via IL-15 and TGF-β, presumably major cytokines essential for TRM cell homeostasis, sustains CD28H expression on T cells. The ligand B7-H5 is constitutively expressed on normal epithelium of human oral-gastrointestinal tracts. In human cancers, CD28H is preferentially present on tumor infiltrating lymphocytes (TILs) with TRM features and identifies a TRM subset with less cytotoxicity. Taken together, our studies suggest that the CD28H/B7-H5 pathway involves the interactions between TRM cells and epithelium, and could be important for human TRM homeostasis and function.

    更新日期:2019-11-01
  • Versican modulates tumor-associated macrophage properties to stimulate mesothelioma growth.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Apostolos G Pappas,Sophia Magkouta,Ioannis S Pateras,Ioannis Skianis,Charalampos Moschos,Maria Eleni Vazakidou,Katherina Psarra,Vassilis G Gorgoulis,Ioannis Kalomenidis

    Versican promotes experimental tumor growth through cell- and non cell-autonomous mechanisms. Its role in mesothelioma progression has not been investigated so far. In this study we investigated the impact of tumor-derived versican in mesothelioma progression and the underlying mechanism of its action. For this purpose, versican-silenced or control ΑΕ17 and ΑΒ1 murine mesothelioma cells were intrapleuraly injected into syngeneic mice, in order to create pleural mesotheliomas and pleural effusions. Intratumoral and pleural immune subsets were assessed using flow cytometry. Mesothelioma cells were co-cultured with syngeneic macrophages to examine versican's impact on their interaction and endothelial cells to assess the effect of versican in endothelial permeability. Versican expression was assessed in human mesotheliomas and mesothelioma-related pleural effusions and benign pleural tissue and effusions. We observed that, versican silencing reduced mesothelioma mass and pleural fluid volume by affecting tumor cell proliferation and apoptosis in vivo, while tumor cell growth remained intact in vitro, and limited pleural vascular permeability. Mice harboring versican-deficient tumors presented fewer tumor/pleural macrophages and neutrophils, and fewer pleural T-regulatory cells, compared to the control animals. Macrophages co-cultured with versican-deficient mesothelioma cells were polarized towards M1 anti-tumor phenotype and demonstrated increased tumor cell phagocytic capacity, compared to macrophages co-cultured with control tumor cells. In co-culture, endothelial monolayer permeability was less effectively stimulated by versican-deficient cells than control cells. Versican was over-expressed in human mesothelioma tissue and mesothelioma-associated effusion. In conclusion, tumor cell-derived versican stimulates mesothelioma progression by shaping a tumor friendly inflammatory milieu, mainly by blunting macrophage anti-tumor activities.

    更新日期:2019-11-01
  • B cells in esophago-gastric adenocarcinoma are highly differentiated, organize in tertiary lymphoid structures and produce tumor-specific antibodies.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Hans A Schlößer,Martin Thelen,Axel Lechner,Kerstin Wennhold,Maria A Garcia-Marquez,Sacha I Rothschild,Elena Staib,Thomas Zander,Dirk Beutner,Birgit Gathof,Ramona Gilles,Engin Cukuroglu,Jonathan Göke,Alexander Shimabukuro-Vornhagen,Uta Drebber,Alexander Quaas,Christiane J Bruns,Arnulf H Hölscher,Michael S Von Bergwelt-Baildon

    Tumor-infiltrating lymphocytes (TILs) are correlated to prognosis of several kinds of cancer. Most studies focused on T cells, while the role of tumor-associated B cells (TABs) has only recently gained more attention. TABs contain subpopulations with distinct functions, potentially promoting or inhibiting immune responses. This study provides a detailed analysis of TABs in gastro-esophageal adenocarcinoma (EAC). Flow cytometric analyses of single cell suspensions of tumor samples, mucosa, lymph nodes and peripheral blood mononuclear cells (PBMC) of EAC patients and healthy controls revealed a distinct B cell compartment in cancer patients. B cells were increased in tumor samples and subset-analyses of TILs showed increased proportions of differentiated and activated B cells and an enrichment for follicular T helper cells. Confocal microscopy demonstrated that TABs were mainly organized in tertiary lymphoid structures (TLS), which resemble lymphoid follicles in secondary lymphoid organs. A panel of 34 tumor-associated antigens (TAAs) expressed in EAC was identified based on public databases and TCGA data to analyze tumor-specific B cell responses using a LUMINEXTM bead assay and flow cytometry. Structural analyses of TLS and the detection of tumor-specific antibodies against one or more TAAs in 48.1% of analyzed serum samples underline presence of anti-tumor B cell responses in EAC. Interestingly, B cells were decreased in tumors with expression of Programmed Death Ligand 1 or impaired HLA-I expression. These data demonstrate that anti-tumor B cell responses are an additional and underestimated aspect of EAC. Our results are of immediate translational relevance to emerging immunotherapies.

    更新日期:2019-11-01
  • Integrated molecular and immunophenotypic analysis of NK cells in anti-PD-1 treated metastatic melanoma patients.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Hansol Lee,Camelia Quek,Ines Silva,Annie Tasker,Marcel Batten,Helen Rizos,Su Yin Lim,Tuba Nur Gide,Ping Shang,Grace H Attrill,Jason Madore,Jarem Edwards,Matteo S Carlino,Alexander Guminski,Robyn P M Saw,John F Thompson,Peter M Ferguson,Umaimainthan Palendira,Alexander M Menzies,Georgina V Long,Richard A Scolyer,James S Wilmott

    Purpose: Anti-PD-1 therapy has revolutionized the treatment and improved the survival of stage IV melanoma patients. However, almost half of the patients fail to respond due to immune evasive mechanism. A known mechanism is the downregulation of major histocompatibility complex (MHC) class I expression, which prevents T cell recognition of the tumor. This study determined the relationship between natural killer (NK) cell numbers and clinical response to anti-PD-1 therapy in metastatic melanoma. Experimental Design: Twenty-five anti-PD-1 treated metastatic melanoma patients were categorized into responders (complete response (CR)/partial response (PR)/stable disease (SD) ≥ 6 mo, n = 13) and non-responders (SD < 6 days/progressive disease (PD), n = 12) based on RECIST response. Whole transcriptome sequencing and multiplex immunofluorescent staining were performed on pre-treatment and on a subset of early during treatment tumor samples. Spatial distribution analysis was performed on multiplex immunofluorescent images to determine the proximity of NK cells to tumor cells. Flow cytometry was used to confirm NK phenotypes in lymph node metastases of treatment naïve melanoma patients (n = 5). Cytotoxic assay was performed using NK cells treated with anti-PD-1 or with isotype control and co-cultured with 3 different melanoma cell lines and with K562 cells (leukemia cell line). Results: Differential expression analysis identified nine upregulated NK cell specific genes (adjusted p < 0.05) in responding (n = 11) versus non-responding patients (n = 10). Immunofluorescent staining of biopsies confirmed a significantly higher density of intra- and peri-tumoral CD16+ and granzyme B + NK cells in responding patients (p < 0.05). Interestingly, NK cells were in closer proximity to tumor cells in responding PD-1 treated patients compared to non-responding patients. Patients who responded to anti-PD-1 therapy, despite MHC class I loss had higher NK cell densities than patients with low MHC class I expression. Lastly, functional assays demonstrated PD-1 blockade induces an increase in NK cells' cytotoxicity. Conclusions: A higher density of tumoral NK cells is associated with response to anti-PD-1 therapy. NK cells may play an important role in mediating response to anti-PD-1 therapy, including in a subset of tumors downregulating MHC class I expression.

    更新日期:2019-11-01
  • Acute myeloid leukemia and NK cells: two warriors confront each other.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Aroa Baragaño Raneros,Carlos López-Larrea,Beatriz Suárez-Álvarez

    Acute myeloid leukemia (AML) is a heterogeneous disease whose therapies currently show elevated toxicity and a high rate of relapse. Recently, the burgeoning of new anti-tumor therapeutic strategies aimed at enhancing the immune response has pushed natural killer cells (NKs) into the spotlight. These cells are powerful warriors that can bring about the lysis of tumor cells through their cytotoxic ability. However, tumor cells have developed strategies to evade recognition mediated by NKs. Here, we review the mechanisms triggered by AML cells and discuss the emerging immunotherapeutic strategies that potentiate the anti-tumor functions of NKs.

    更新日期:2019-11-01
  • Clinical characterization of colitis arising from anti-PD-1 based therapy.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Daniel Y Wang,Meghan J Mooradian,DaeWon Kim,Neil J Shah,Sarah E Fenton,Robert M Conry,Rutika Mehta,Ann W Silk,Alice Zhou,Margaret L Compton,Rami N Al-Rohil,Sunyoung Lee,Amber L Voorhees,Lisa Ha,Svetlana McKee,Jacqueline T Norrell,Janice Mehnert,Igor Puzanov,Jeffrey A Sosman,Sunandana Chandra,Geoffrey T Gibney,Suthee Rapisuwon,Zeynep Eroglu,Ryan Sullivan,Douglas B Johnson

    Colitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not well-characterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy ("monotherapy") or combined with ipilimumab ("combination therapy") were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p < 0.0001), received higher steroid doses (median prednisone equivalent 1.5 mg/kg vs 1.0 mg/kg, p = 0.0015) and experienced longer steroid tapers (median 6.0 vs 4.0 weeks, p = 0.0065) compared to monotherapy. Infliximab use and steroid-dose escalation occurred more frequently in the combination therapy cohort compared to monotherapy. Nearly all patients had resolution of their symptoms although one patient died from complications. Anti-PD-1 associated colitis has a variable clinical presentation, and is more frequent and severe when associated with combination therapy. This variability in checkpoint-inhibitor associated colitis suggests that further optimization of treatment algorithms is needed.

    更新日期:2019-11-01
  • Therapeutic vaccination using minimal HPV16 epitopes in a novel MHC-humanized murine HPV tumor model.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Sebastian Kruse,Marleen Büchler,Philipp Uhl,Max Sauter,Philipp Scherer,Tammy C T Lan,Samantha Zottnick,Alexandra Klevenz,Ruwen Yang,Frank Rösl,Walter Mier,Angelika B Riemer

    Therapeutic vaccination as a treatment option for HPV-induced cancers is actively pursued because the two HPV proteins E6 and E7 represent ideal targets for immunotherapy, as they are non-self and expressed in all tumor stages. MHC-humanized mice are valuable tools for the study of therapeutic cancer vaccines - given the availability of a suitable tumor model. Here, we present for the first time an HPV16 tumor model suitable for fully MHC-humanized A2.DR1 mice, PAP-A2 cells, which in contrast to existing HPV16 tumor models allows the exclusive study of HLA-A2- and DR1-mediated immune responses, without any interfering murine MHC-presented epitopes. We used several HPV16 epitopes that were shown to be presented on human cervical cancer cells by mass spectrometry for therapeutic anti-tumor vaccination in the new tumor model. All epitopes were immunogenic when rendered amphiphilic by incorporation into a molecule containing stearic acids. Prophylactic and therapeutic vaccination experiments with the epitope E7/11-19 demonstrated that effective immune responses could be induced with these vaccination approaches in A2.DR1 mice. Interestingly, the combination of E7/11-19 with other immunogenic HPV16 E6/E7 epitopes caused a reduction of vaccine efficacy, although all tested combinations resulted in a survival benefit. In summary, we present the first HPV16 tumor model for exclusive studies of HLA-A2-mediated anti-HPV tumor immune responses and show anti-tumor efficacy of minimal epitope vaccines.

    更新日期:2019-11-01
  • BRAF and MEK inhibitors differentially affect nivolumab-induced T cell activation by modulating the TCR and AKT signaling pathways.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Peng Yue,Taylor Harper,Silvia M Bacot,Monica Chowdhury,Shiowjen Lee,Adovi Akue,Mark A Kukuruga,Tao Wang,Gerald M Feldman

    Immune checkpoint inhibitors (ICIs) such as the anti-PD-1 antibody Nivolumab, achieve remarkable clinical efficacy in patients with late stage cancers. However, only a small subset of patients benefit from this therapy. Numerous clinical trials are underway testing whether combining ICIs with other anti-cancer therapies can increase this response rate. For example, anti-PD-1/PD-L1 therapy combined with MAP kinase inhibition using BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) are in development for treatment of late stage melanomas. However, the benefits and underlying mechanisms of these combinatorial therapies remain unclear. In the current study, we assess the effects of MAPK inhibition on Nivolumab-induced T cell responses. Using an in vitro mixed lymphocyte reaction assay, we demonstrate that Nivolumab-induced T cell activation is highly heterogeneous. While BRAFi inhibits Nivolumab-induced cytokine production, T cell proliferation, activation markers (CD69, CD25), and Granzyme B in a substantial proportion of donor pairs, a small subset of donor pairs shows an additive effect. MEKi alone significantly inhibits Nivolumab-induced T cell activation; the addition of BRAFi significantly enhances this inhibitory effect. Mechanistically, the effects of BRAFi and/or MEKi on Nivolumab-induced T cell activation may be due to alteration of the activation of the AKT and T cell receptor (TCR) signaling pathways. Our results suggest that MAPK inhibition may not provide a clinical benefit for most melanoma patients being treated with anti-PD-1 therapy.

    更新日期:2019-11-01
  • Genetic associations of T cell cancer immune response with tumor aggressiveness in localized prostate cancer patients and disease reclassification in an active surveillance cohort.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Qinchuan Wang,Justin R Gregg,Jian Gu,Yuanqing Ye,David W Chang,John W Davis,Timothy C Thompson,Jeri Kim,Christopher J Logothetis,Xifeng Wu

    Determining prostate cancer (PCa) aggressiveness and reclassification are critical events during the treatment of localized disease and for patients undergoing active surveillance (AS). Since T cells play major roles in cancer surveillance and elimination, we aimed to identify genetic biomarkers related to T cell cancer immune response which are predictive of aggressiveness and reclassification risks in localized PCa. The genotypes of 3,586 single nucleotide polymorphisms (SNPs) from T cell cancer immune response pathways were analyzed in 1762 patients with localized disease and 393 who elected AS. The aggressiveness of PCa was defined according to pathological Gleason score (GS) and D'Amico criteria. PCa reclassification was defined according to changes in GS or tumor characteristics during subsequent surveillance biopsies. Functional characterization and analysis of immune phenotypes were also performed. In the localized PCa cohort, seven SNPs were significantly associated with the risk of aggressive disease. In the AS cohort, another eight SNPs were identified as predictors for aggressiveness and reclassification. Rs1687016 of PSMB8 was the most significant predictor of reclassification. Cumulative analysis showed that a genetic score based on the identified SNPs could significantly predict risk of D'Amico high risk disease (P-trend = 2.4E-09), GS4 + 3 disease (P-trend = 1.3E-04), biochemical recurrence (P-trend = 0.01) and reclassification (P-trend = 0.01). In addition, the rs34309 variant was associated with functional somatic mutations in the PI3K/PTEN/AKT/MTOR pathway and tumor lymphocyte infiltration. Our study provides plausible evidence that genetic variations in T cell cancer immune response can influence risks of aggressiveness and reclassification in localized PCa, which may lead to additional biological insight into these outcomes. Abbreviations: PCa, prostate cancer; AS, active surveillance; GS, Gleason score; PSA, prostate specific antigen; TCGA, The Cancer Genome Atlas; SNP, single nucleotide polymorphisms; UFG, unfavorable genotype.

    更新日期:2019-11-01
  • Identification and editing of stem-like cells in methylcholanthrene-induced sarcomas.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Emilie T E Gross,Carlos D Peinado,Yujin Jung,Semi Han,Beichen Liu,Endi K Santosa,Jack D Bui

    The cancer stem cell (CSC) paradigm posits that specific cells within a tumor, so-called CSC-like cells, have differing levels of tumorigenicity and chemoresistance. Original studies of CSCs identified them in human cancers and utilized mouse xenograft models to define the cancer initiating properties of these cells, thereby hampering the understanding of how immunity could affect CSCs. Indeed, few studies have characterized CSCs in the context of cancer immunoediting, and it is currently not clear how immunity could impact on the levels or stem-like behavior of CSCs. Using the well-studied 3'methylcholanthrene (MCA) model of primary sarcoma formation, we have defined a CSC-like population within MCA-induced sarcomas as expressing high levels of stem cell antigen-1 (Sca-1) and low levels of CD90. These Sca-1+CD90- CSC-like cells had higher tumor initiating ability, could spontaneously give rise to Sca-1-negative cells, and formed more sarcospheres than corresponding non-CSC-like cells. Moreover, when examining MCA-induced sarcomas that were in the equilibrium phase of cancer growth, higher levels of CSC-like cells were found compared to MCA-induced sarcomas in the escape phase of cancer progression. Notably, CSC-like cells also emerged during escape from anti-PD-1 or anti-CTLA4 therapy, thus suggesting that CSC-like cells could evade immune therapy. Finally, we demonstrate that paradoxically, interferon (IFN)-γ produced in vivo by immune cells could promote the emergence of CSC-like cells. Our findings define the existence of a Sca1+CD90- CSC-like population in the MCA-sarcoma model capable of differentiation, tumorsphere formation, and increased tumor initiation in vivo. These cells may also act as mediators of immune resistance during cancer immunoediting and immune therapy.

    更新日期:2019-11-01
  • Predictors of disease aggressiveness influence outcome from immunotherapy treatment in renal clear cell carcinoma.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Yasmin Kamal,Chao Cheng,H Robert Frost,Christopher I Amos

    Renal clear cell carcinoma (RCC) is the most common type of kidney cancer and has a high propensity for metastasis. While treatment with immune checkpoint inhibitors, such as anti-PD-1, have shown modest improvements in survival for RCC, it is difficult to identify responders from non-responders. Attempts to elucidate the mechanisms associated with differential response to checkpoint inhibitors have been limited by small sample size making it difficult to detect meaningful associations. We utilized existing large datasets from The Cancer Genome Atlas (TCGA) to first find predictors of disease aggressiveness in the tumor microenvironment (TME) and hypothesized that these same predictors may influence response to immunotherapy. We found primary metastatic (M1-stage IV) tumors exhibit high immune infiltration, and high TP53-inactivation induced senescence activity compared to non-metastatic (M0-Stage I/II) tumors. Moreover, some TME features inferred from deconvolution algorithms, which differ between M0 and M1 tumors, also influence overall survival. A focused analysis identified interactions between tumor TP53-inactivation induced senescence activity and expression of inflammatory molecules in pre-treatment RCC tumors, which predict both change in tumor size and response to checkpoint blockade therapy. We also noted frequency of inactivating mutations in the protein polybromo-1 (PBRM1) gene was found to be negatively associated with TP53-inactivation induced senescence enrichment. Our findings suggest a mechanism by which tumor TP53-inactivation induced senescence can modulate the TME and thereby influence outcome from checkpoint blockade therapy.

    更新日期:2019-11-01
  • Sepsis inhibits tumor growth in mice with cancer through Toll-like receptor 4-associated enhanced Natural Killer cell activity.
    Oncoimmunology (IF 5.333) Pub Date : null
    Clara Vigneron,Adrien Mirouse,Hamid Merdji,Christophe Rousseau,Clément Cousin,Fanny Alby-Laurent,Jean-Paul Mira,Jean-Daniel Chiche,Jean-François Llitjos,Frédéric Pène

    Sepsis-induced immune dysfunctions are likely to impact on malignant tumor growth. Sequential sepsis-then-cancer models of tumor transplantation in mice recovering from sepsis have shown that the post-septic immunosuppressive environment was able to promote tumor growth. We herein addressed the impact of sepsis on pre-established malignancy in a reverse cancer-then sepsis experimental model. Mice previously inoculated with MCA205 fibrosarcoma cells were subjected to septic challenges by polymicrobial peritonitis induced by cecal ligation and puncture or endotoxinic shock. The anti-tumoral immune response was assessed through the distribution of tumor-infiltrating immune cells, as well as the functions of cytotoxic cells. As compared to sham surgery, polymicrobial sepsis dampened malignant tumor growth in wild-type (WT) mice, but neither in Toll-like receptor 4 (Tlr4)-/- nor in Myd88-/- mice. Similar tumor growth inhibition was observed following a LPS challenge in WT mice, suggesting a regulatory role of Tlr4 in this setting. The low expression of MHC class 1 onto MCA205 cells suggested the involvement of Natural Killer (NK) cells in sepsis-induced tumor inhibition. Septic insults applied to mice with cancer promoted the main anti-tumoral NK functions of IFNγ production and degranulation. The anti-tumoral properties of NK cells obtained from septic mice were exacerbated when cultured with MHC1low MCA205 or YAC-1 cells. These results suggest that sepsis may harbor dual effects on tumor growth depending on the sequential experimental model. When applied in mice with cancer, sepsis prevents tumor growth in a Tlr4-dependent manner by enhancing the anti-tumoral functions of NK cells.

    更新日期:2019-11-01
  • Enhancing direct cytotoxicity and response to immune checkpoint blockade following ionizing radiation with Wee1 kinase inhibition.
    Oncoimmunology (IF 5.333) Pub Date : null
    Priya Patel,Lily Sun,Yvette Robbins,Paul E Clavijo,Jay Friedman,Christopher Silvin,Carter Van Waes,John Cook,James Mitchell,Clint Allen

    Tumor cells activate the G2/M cell cycle checkpoint in response to ionizing radiation (IR) and effector immune cell-derived granzyme B to facilitate repair and survival. Wee1 kinase inhibition reverses the ability of tumor cells to pause at G2/M. Here, we hypothesized that AZD1775, a small molecule inhibitor of Wee1 kinase, could sensitize tumor cells to IR and T-lymphocyte killing and improve responses to combination IR and programmed death (PD)-axis immune checkpoint blockade (ICB). Multiple models of head and neck carcinoma, lung carcinoma and melanoma were used in vitro and in vivo to explore this hypothesis. AZD1775 reversed G2/M cell cycle checkpoint activation following IR, inducing cell death. Combination IR and AZD1775 induced accumulation of DNA damage in M-phase cells and was rescued with nucleoside supplementation, indicating mitotic catastrophe. Combination treatment enhanced control of syngeneic MOC1 tumors in vivo, and on-target effects of systemic AZD1775 could be localized with targeted IR. Combination treatment enhanced granzyme B-dependent T-lymphocyte killing through reversal of additive G2/M cell cycle block induced by IR and granzyme B. Combination IR and AZ1775-enhanced CD8+ cell-dependent MOC1 tumor growth control and rate of complete rejection of established tumors in the setting of PD-axis ICB. Functional assays demonstrated increased tumor antigen-specific immune responses in sorted T-lymphocytes. The combination of IR and AZD1775 not only lead to enhanced tumor-specific cytotoxicity, it also enhanced susceptibility to T-lymphocyte killing and responses to PD-axis ICB. These data provide the pre-clinical rationale for the combination of these therapies in the clinical trial setting.

    更新日期:2019-11-01
  • Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy.
    Oncoimmunology (IF 5.333) Pub Date : null
    Sara Verdura,Elisabet Cuyàs,Begoña Martin-Castillo,Javier A Menendez

    The development of a single immuno-metabolic adjuvant capable of modulating, in the appropriate direction and intensity, the complex antagonistic and symbiotic interplays between tumor cells, immune cells, and the gut microbiota may appear pharmacologically implausible. Metformin might help solve this conundrum and beneficially impact the state of cancer-immune system interactions.

    更新日期:2019-11-01
  • CD80 expression promotes immune surveillance in Barrett's metaplasia.
    Oncoimmunology (IF 5.333) Pub Date : null
    Melania Scarpa,Matteo Fassan,Andromachi Kotsafti,Stefano Realdon,Luigi Dall'Olmo,Tiziana Morbin,Francesco Cavallin,Luca Saadeh,Matteo Cagol,Rita Alfieri,Carlo Castoro,Massimo Rugge,Ignazio Castagliuolo,Marco Scarpa

    Esophageal adenocarcinoma (EAC) is the final step of a pathway starting with esophageal reflux disease, Barrett's metaplasia and Barrett's dysplasia. Positive costimulatory ligands such as CD80 have been suggested to contribute to anti-tumor T-cell efficacy. Here we report for the first time the role of CD80 in the inflammatory esophageal carcinogenesis and characterize the immune environment of EAC. Mucosa samples from cancer were obtained during esophagectomy from patients affected by EAC. Fresh biopsies were obtained from patients who underwent endoscopy for screening or follow-up. A rodent model of reflux induced esophageal carcinogenesis was created with an esophago-gastro-jejunostomy. CD80 expression was increased in epithelial cells during metaplasia in the inflammatory esophageal carcinogenesis cascade. Cd80 null mice as well as WT mice that received antiCD80 antibodies showed a higher rate of dysplasia and KI-67+ cells. These results suggest that CD80 mediates an active immune surveillance process in early inflammation-driven esophageal carcinogenesis.

    更新日期:2019-11-01
  • Constitutively active GSK3β as a means to bolster dendritic cell functionality in the face of tumour-mediated immune suppression.
    Oncoimmunology (IF 5.333) Pub Date : null
    Marta López González,Dinja Oosterhoff,Jelle J Lindenberg,Ioanna Milenova,Sinead M Lougheed,Tania Martiáñez,Henk Dekker,Dafne Carolina Alves Quixabeira,Basav Hangalapura,Jos Joore,Sander R Piersma,Victor Cervera-Carrascon,Joao Manuel Santos,Rik J Scheper,Henk M W Verheul,Connie R Jiménez,Rieneke Van De Ven,Akseli Hemminki,Victor W Van Beusechem,Tanja D De Gruijl

    In patients with cancer, the functionality of Dendritic Cells (DC) is hampered by high levels of tumor-derived suppressive cytokines, which interfere with DC development and maturation. Poor DC development can limit the efficacy of immune checkpoint blockade and in vivo vaccination approaches. Interference in intracellular signaling cascades downstream from the receptors of major tumor-associated suppressive cytokines like IL-10 and IL-6, might improve DC development and activation, and thus enhance immunotherapy efficacy. We performed exploratory functional screens on arrays consisting of >1000 human kinase peptide substrates to identify pathways involved in DC development and its inhibition by IL-10 or IL-6. The resulting alterations in phosphorylation of the kinome substrate profile pointed to glycogen-synthase kinase-3β (GSK3β) as a pivotal kinase in both DC development and suppression. GSK3β inhibition blocked human DC differentiation in vitro, which was accompanied by decreased levels of IL-12p70 secretion, and a reduced capacity for T cell priming. More importantly, adenoviral transduction of monocytes with a constitutively active form of GSK3β induced resistance to the suppressive effects of IL-10 and melanoma-derived supernatants alike, resulting in improved DC development, accompanied by up-regulation of co-stimulatory markers, an increase in CD83 expression levels in mature DC, and diminished release of IL-10. Moreover, adenovirus-mediated intratumoral manipulation of this pathway in an in vivo melanoma model resulted in DC activation and recruitment, and in improved immune surveillance and tumor control. We propose the induction of constitutive GSK3β activity as a novel therapeutic means to bolster DC functionality in the tumor microenvironment.

    更新日期:2019-11-01
  • Inhibition of Hedgehog signaling reprograms the dysfunctional immune microenvironment in breast cancer.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-07
    Ann Hanna,Brandon J Metge,Sarah K Bailey,Dongquan Chen,Darshan S Chandrashekar,Sooryanarayana Varambally,Rajeev S Samant,Lalita A Shevde

    Host responses to tumor cells include tumor suppressing or promoting mechanisms. We sought to detail the effect of Hedgehog (Hh) pathway inhibition on the composition of the mammary tumor immune portfolio. We hypothesized that Hh signaling mediates a crosstalk between breast cancer cells and macrophages that dictates alternative polarization of macrophages and consequently supports a tumor-promoting microenvironment. We used an immunocompetent, syngeneic mouse mammary cancer model to inhibit Hh signaling with the pharmacological inhibitor, Vismodegib. Using molecular and functional assays, we identified that Hedgehog (Hh) signaling mediates a molecular crosstalk between mammary cancer cells and macrophages that culminates in alternative polarization of macrophages. We carried out an unbiased kinomics and genomics assessment to unravel changes in global kinomic and gene signatures impacted by Hh signaling. Our investigations reveal that in an immunocompetent mammary cancer model, the administration of Vismodegib led to changes in the portfolio of tumor-infiltrating immune cells. This was characterized by a marked reduction in immune-suppressive innate and adaptive cells concomitant with an enrichment of cytotoxic immune cells. Breast cancer cells induce M2 polarization of macrophages via a crosstalk mediated by Hh ligands that alters critical kinomic and genomic signatures. Macrophage depletion improved the benefit of Hedgehog inhibition on eliciting an immunogenic, pro-inflammatory profile. We define a novel role for Hh signaling in disabling anti-tumor immunity. Inhibition of Hh signaling presents with dual advantages of tumor cell-targeting as well as re-educating a dysfunctional tumor microenvironment.

    更新日期:2019-11-01
  • Critical role of post-transcriptional regulation for IFN-γ in tumor-infiltrating T cells.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Fiamma Salerno,Aurelie Guislain,Julian J Freen-Van Heeren,Benoit P Nicolet,Howard A Young,Monika C Wolkers

    Protective T cell responses against tumors require the production of Interferon gamma (IFN-γ). However, tumor-infiltrating T cells (TILs) gradually lose their capacity to produce IFN-γ and therefore fail to clear malignant cells. Dissecting the underlying mechanisms that block cytokine production is thus key for improving T cell products. Here we show that although TILs express substantial levels of Ifng mRNA, post-transcriptional mechanisms impede the production of IFN-γ protein due to loss of mRNA stability. CD28 triggering, but not PD1 blocking antibodies, effectively restores the stability of Ifng mRNA. Intriguingly, TILs devoid of AU-rich elements within the 3'untranslated region maintain stabilized Ifng mRNA and produce more IFN-γ protein than wild-type TILs. This sustained IFN-γ production translates into effective suppression of tumor outgrowth, which is almost exclusively mediated by direct effects on the tumor cells. We therefore conclude that post-transcriptional mechanisms could be modulated to potentiate effective T cell therapies in cancer.

    更新日期:2019-11-01
  • Circulating NKp46+ Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Emilie Picard,Yann Godet,Caroline Laheurte,Magalie Dosset,Jeanne Galaine,Laurent Beziaud,Romain Loyon,Laura Boullerot,Elodie Lauret Marie Joseph,Laurie Spehner,Marion Jacquin,Guillaume Eberst,Béatrice Gaugler,Françoise Le Pimpec-Barthes,Elizabeth Fabre,Virginie Westeel,Anne Caignard,Christophe Borg,Olivier Adotévi

    Natural killer (NK) cells are innate effector lymphocytes widely involved in cancer immunosurveillance. In this study, we described three circulating NK cell subsets in patients with non-small cell lung cancer (NSCLC). Compared to healthy donors (HD), lower rate of the cytotoxic CD56dim CD16+ NK cells was found in NSCLC patients (76.1% vs 82.4%, P = 0.0041). In contrast, the rate of CD56bright NK cells was similar between patients and HD. We showed in NSCLC patients a higher rate of a NK cell subset with CD56dim CD16- phenotype (16.7% vs 9.9% P = 0.0001). The degranulation property and cytokines production were mainly drive by CD56dim CD16- NK cell subset in patients. Analysis of natural cytotoxicity receptors (NCRs) expression identified four distinct clusters of patients with distinct NK cell subset profiles as compared to one major cluster in HD. Notably the cluster characterized by a low circulating level of NKp46+ NK cell subsets was absent in HD. We showed that the rate of circulating NKp46+ CD56dim CD16+ NK cells influenced the patients' survival. Indeed, the median overall survival in patients exhibiting high versus low level of this NK cell subset was 16 and 27 months respectively (P = 0.02). Finally, we demonstrated that blocking NKp46 receptor in vitro was able to restore spontaneous tumor specific T cell responses in NSCLC patients. In conclusion, this study showed a distinct distribution and phenotype of circulating NK cell subsets in NSCLC. It also supports the regulatory role of NKp46+ NK cell subset in NSCLC patients.

    更新日期:2019-11-01
  • Mannan-binding lectin suppresses growth of hepatocellular carcinoma by regulating hepatic stellate cell activation via the ERK/COX-2/PGE2 pathway.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    Junru Li,Huifang Li,Yu Yu,Yan Liu,Yunzhi Liu,Qiang Ma,Liyun Zhang,Xiao Lu,Xiang-Yang Wang,Zhengliang Chen,Daming Zuo,Jia Zhou

    Mannan binding lectin (MBL), initially known to activate the complement lectin pathway and defend against infection, was recently shown to be potentially involved in the development of several types of cancer; however, its exact role in cancers, especially its effect on tumor microenvironment remain largely unknown. Here, using a murine hepatocellular carcinoma (HCC) model, we showed that MBL was a component of liver microenvironment and MBL-deficient (MBL-/-) mice exhibited an enhanced tumor growth compared with wild-type (WT) mice. This phenomenon was associated with elevation of myeloid derived suppressed cells (MDSCs) in tumor tissue of MBL-/- mice. MBL deficiency also resulted in an increase of activated hepatic stellate cells (HSCs), which showed enhanced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Pharmacological inhibition of COX-2 in vivo partially abrogated the MBL deficiency-promoted tumor growth and MDSC accumulation. Mechanistic studies revealed that MBL could interact directly with HSCs and inhibit HCC-induced HSCs activation via downregulating the extracellular signal-regulated kinase (ERK)/COX-2/PGE2 signaling pathway. Furthermore, MBL-mediated suppression of HCC is validated by administration of MBL-expressing, liver-specific adeno-associated virus (AAV), which significantly inhibited HCC progression in MBL-/- mice. Taken together, these data reveal that MBL may impact on tumor development by shaping the tumor microenvironment via its interaction with the local stromal cells, and also suggests its potential therapeutic use for the treatment of HCC.

    更新日期:2019-11-01
  • IL-33 increases ST2+ Tregs and promotes metastatic tumour growth in the lungs in an amphiregulin-dependent manner.
    Oncoimmunology (IF 5.333) Pub Date : 2019-02-05
    E C Halvorsen,S E Franks,B J Wadsworth,B T Harbourne,R A Cederberg,C A Steer,I Martinez-Gonzalez,J Calder,W W Lockwood,K L Bennewith

    Regulatory T cells (Tregs) facilitate primary and metastatic tumour growth through the suppression of anti-tumour immunity. Emerging evidence suggests a distinct role for Tregs in mediating tissue repair and barrier integrity in the lungs by IL-33 mediated production of the growth factor amphiregulin (AREG). Dependent on the type of cancer and local microenvironment, AREG may induce tumour cell proliferation, invasion, migration or resistance to apoptosis by signaling through the epidermal growth factor receptor (EGFR). We have found that IL-33 is dramatically increased in and around metastatic tumour foci in the lungs of mice bearing orthotopic murine mammary tumours. We observed that Tregs express significantly more of the IL-33 receptor, ST2, relative to conventional T cells, that ST2+ Tregs accumulate in the lungs of metastatic tumour-bearing mice, and that ST2+ Tregs produce significantly more AREG than ST2- Tregs. The intranasal administration of recombinant IL-33 increased the proportion of AREG producing ST2+ Tregs and enhanced the level of phosphorylated EGFR in the metastatic lungs. While recombinant AREG did not impact mammary tumour cell proliferation in vitro despite inducing a dose-dependent increase in phosphorylated EGFR, intranasal administration of AREG resulted in a ten-fold increase in pulmonary metastatic tumour burden in vivo. Further, the intranasal administration of recombinant IL-33 significantly increased metastatic tumour burden in the lungs in an amphiregulin-dependent manner. These data identify ST2+ Tregs as a microenvironmental source of AREG in the lungs of mice with orthotopic metastatic mammary tumours and highlight an important role for AREG in promoting metastatic tumour growth in the lungs.

    更新日期:2019-11-01
  • Virotherapy-recruited PMN-MDSC infiltration of mesothelioma blocks antitumor CTL by IL-10-mediated dendritic cell suppression.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Zhiwu Tan,Li Liu,Mei Sum Chiu,Ka-Wai Cheung,Chi Wing Yan,Zhe Yu,Boon Kiat Lee,Wan Liu,Kwan Man,Zhiwei Chen

    Antitumor cytotoxic T lymphocytes (CTLs) are essential for immune surveillance, yet the blockade of eliciting such CTLs during oncolytic virotherapy remains incompletely understood. Here, we show that oncolysis of mesothelioma by modified vaccinia Tiantan (MVTT) induces damage-associated molecular patterns exposure. Although MVTT leads to regression of established mesothelioma dose-dependently, antitumor CTLs are rarely induced. Mechanistically, MVTT virotherapy generates C-X-C chemokines that recruit CXCR2-expressing polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into tumor microenvironment, where they suppress dendritic cells (DCs) by producing IL-10 and halt CTL responses. During the virotherapy, however, depletion of PMN-MDSCs but not of monocytic (M)-MDSCs results in the induction of potent antitumor CTLs that not only eradicate established mesothelioma but also prevent the second tumor challenge. Our findings suggest that vaccinia virotherapy may combine strategies that prevent the chemotactic recruitment of PMN-MDSCs, block their suppression on DCs or deplete PMN-MDSCs in order to induce potent CTLs for tumor eradication.

    更新日期:2019-11-01
  • Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Junseong Park,Chang Gon Kim,Jin-Kyoung Shim,Jong Hoon Kim,Hoyoung Lee,Jae Eun Lee,Min Hwan Kim,Keeok Haam,Inkyung Jung,Su-Hyung Park,Jong Hee Chang,Eui-Cheol Shin,Seok-Gu Kang

    Background: Although programmed death-1 (PD-1) blockade is effective in treating several types of cancer, the efficacy of this agent in glioblastoma (GBM) is largely unknown. Methods: We evaluated therapeutic effects of anti-PD-1, temozolomide (TMZ), and their combination in an orthotopic murine GBM model. The phenotype, number, and composition of lymphocytes were evaluated using flow cytometry. Transcriptional profiles of tumor tissues were analyzed using microarrays. Generation of antitumor immunological memory was investigated upon rechallenge. Results: Combined treatment with anti-PD-1 and TMZ yielded synergistic antitumor efficacy in the presence of donor-originated PD-1+CD8+ T cells in vitro, necessitating in vivo validation. Whereas TMZ did not rescue GBM-implanted mice, anti-PD-1 completely eradicated GBM in 44.4% of mice, and combination of anti-PD-1 and TMZ in all mice. Anti-PD-1 significantly increased the number of tumor-infiltrating lymhpocytes (TILs), and reduced frequencies of exhausted T cells and regulatory T cells. However, combining TMZ with anti-PD-1 significantly decreased the number of TILs, which was also observed with TMZ treatment alone. A transcriptome analysis of tumor tissues revealed that anti-PD-1 monotherapy perturbed immune-related genes, distinctly with combined therapy. Upon rechallenge, tumor growth was not observed in mice cured by anti-PD-1 monotherapy, whereas tumors regrew in the combination group. Furthermore, an analysis of peripheral blood revealed that antitumor memory T cells were generated in mice cured by anti-PD-1 monotherapy, not in the combination group. Conclusion: PD-1 blockade induces long-term therapeutic response, and combination with TMZ further enhances antitumor efficacy. However, immunological memory is provoked by anti-PD-1 monotherapy, not by combined therapy.

    更新日期:2019-11-01
  • lncRNA MALAT1 binds chromatin remodeling subunit BRG1 to epigenetically promote inflammation-related hepatocellular carcinoma progression.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Mingyan Huang,Huamin Wang,Xiang Hu,Xuetao Cao

    Hepatocellular carcinoma (HCC) is one type of cancers whose carcinogenesis and progression are closely related to chronic inflammation. Identifying the molecular mechanisms for inflammation-related HCC progression will contribute to improve the efficacy of current therapeutics for HCC patients. Many kinds of epigenetic factors, including long non-coding RNAs (lncRNAs), have been discovered to be important in HCC growth and metastasis. However, how the lncRNAs promote HCC progression and what's the application of lncRNA silencing in vivo in suppressing HCC remain to be further investigated. Here, we found that lncRNA metastasis associated lung adenocarcinoma transcript1 (MALAT1) was upregulated in HCC tumor tissues, and knockdown of MALAT1 suppressed proliferation, cell cycle and invasion of HCC cells in response to lipopolysaccharide (LPS) stimulation. Knockdown of MALAT1 significantly inhibited LPS-induced pro-inflammatory mediators IL-6 and CXCL8 expression in HCC cells, which could be restored by overexpressing MALAT1. Mechanistically, MALAT1 recruited Brahma-related gene 1 (BRG1), a catalytic subunit of chromatin remodeling complex switching/sucrose non-fermentable (SWI/SNF), to the promoter region of IL-6 and CXCL8, and thus facilitated NF-κB to induce the expression of these inflammatory factors. Importantly, in vivo silencing of MALAT1 in HCC tissues inhibited growth of HCC xenografts, and also suppressed the expression of pro-inflammatory factors in HCC tissues accordingly. Our results demonstrate that MALAT1 promotes HCC progression by binding BRG1 to epigenetically enhance inflammatory response in HCC tissues, and silencing of MALAT1 may be a potential approach to the treatment of HCC.

    更新日期:2019-11-01
  • The role of CMV in glioblastoma and implications for immunotherapeutic strategies.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Maryam Rahman,Farhad Dastmalchi,Aida Karachi,Duane Mitchell

    Controversy surrounds the role of cytomegalovirus (CMV) in glioblastoma (GBM). However, several studies have shown that CMV nucleic acids and proteins are present within GBM tumor tissue. CMV has been implicated in GBM pathogenesis by affecting tumor stem cell factors, angiogenesis and immune pathways. Anti-viral therapy has not been found to definitively improve outcomes for patients with GBM. Several studies have leveraged CMV by targeting CMV antigens using ex-vivo expanded T cells or dendritic cell vaccines. The initial results from these studies are promising and larger studies are underway.

    更新日期:2019-11-01
  • Ibrutinib significantly inhibited Bruton's tyrosine kinase (BTK) phosphorylation,in-vitro proliferation and enhanced overall survival in a preclinical Burkitt lymphoma (BL) model.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Yaya Chu,Sanghoon Lee,Tishi Shah,Changhong Yin,Matthew Barth,Rodney R Miles,Janet Ayello,Erin Morris,Lauren Harrison,Carmella Van de Ven,Paul Galardy,Stanton C Goldman,Megan S Lim,Michelle Hermiston,Linda M McAllister-Lucas,Lisa Giulino-Roth,Sherrie L Perkins,Mitchell S Cairo

    Pediatric and adult patients with recurrent/refractory Burkitt lymphoma (BL) continue to have poor outcomes, emphasizing the need for newer therapeutic agents. Bruton's tyrosine kinase (BTK) is activated following B-cell receptor stimulation and in part regulates normal B-cell development. Ibrutinib, a selective and irreversible BTK inhibitor, has been efficacious in chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia, and marginal zone lymphoma. In this study, we investigated the efficacy of ibrutinib alone and in selective adjuvant combinations against BL in-vitro and in a human BL xenografted immune-deficient NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mouse model. Our data demonstrated that phospho-BTK level was significantly reduced in BL cells treated with ibrutinib (p < 0.001). Moreover, we observed a significant decrease in cell proliferation as well as significant decrease in IC50 of ibrutinib in combination with dexamethasone, rituximab, obinutuzumab, carfilzomib, and doxorubicin (p < 0.001). In-vivo studies demonstrated ibrutinib treated mice had a significantly prolonged survival with median survival of mice following ibrutinib treatment (32 days) (24 days) (p < 0.02). In conclusion, our findings demonstrate the significant in-vitro and preclinical in-vivo effects of ibrutinib in BL. Based on our preclinical results in this investigation, there is an on-going clinical trial comparing overall survival in children and adolescents with relapsed/refractory BL treated with chemoimmunotherapy with or without ibrutinib (NCT02703272).

    更新日期:2019-11-01
  • Combination PD-1 blockade and irradiation of brain metastasis induces an effective abscopal effect in melanoma.
    Oncoimmunology (IF 5.333) Pub Date : 2018-12-14
    Lukas W Pfannenstiel,Corey McNeilly,Chaomei Xiang,Kai Kang,Claudia Marcella Diaz-Montero,Jennifer S Yu,Brian R Gastman

    Nearly half of melanoma patients develop brain metastases during the course of their disease. Despite advances in both localized radiation and systemic immunotherapy, brain metastases remain difficult to treat, with most patients surviving less than 5 months from the time of diagnosis. While both treatment regimens have individually shown considerable promise in treating metastatic melanoma, there is interest in combining these strategies to take advantage of potential synergy. In order to study the ability of local radiation and anti-PD-1 immunotherapy to induce beneficial anti-tumor immune responses against distant, unirradiated tumors, we used two mouse models of metastatic melanoma in the brain, representing BRAF mutant and non-mutant tumors. Combination treatments produced a stronger systemic anti-tumor immune response than either treatment alone. This resulted in reduced tumor growth and larger numbers of activated, cytotoxic CD8+ T cells, even in the unirradiated tumor, indicative of an abscopal effect. The immune-mediated effects were present regardless of BRAF status. These data suggest that irradiation of brain metastases and anti-PD-1 immunotherapy together can induce abscopal anti-tumor responses that control both local and distant disease.

    更新日期:2019-11-01
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