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  • Immunoregulation and Clinical Implications of ANGPT2/TIE2+ M-MDSC Signature in Non–Small Cell Lung Cancer
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-22
    Elodie Lauret Marie Joseph; Caroline Laheurte; Marine Jary; Laura Boullerot; Kamal Asgarov; Eléonore Gravelin; Adeline Bouard; Laurie Rangan; Magalie Dosset; Christophe Borg; Olivier Adotévi

    Myeloid-derived suppressor cells (MDSC) promote immunosuppression and are a target in the field of immuno-oncology. Accumulation of MDSCs is associated with poor prognosis and resistance to immunotherapy for several cancers. Here, we describe an accumulation of a subset of circulating monocytic MDSCs (M-MDSC) overexpressing TIE2, the receptor for angiopoietin-2 (ANGPT2), in patients with non–small cell lung cancer (NSCLC). Greater numbers of circulating TIE2+ M-MDSCs were detected in patients with NSCLC compared with healthy subjects, and this accumulation correlated with ANGPT2 concentration in blood. The presence of an ANGPT2-rich environment was associated with impairment of preexisting T-cell responses against tumor-associated antigens (TAA) in patients with NSCLC. We demonstrated that ANGPT2 sensitizes TIE2+ M-MDSCs such that these cells suppress TAA-specific T cells. In patients with NSCLC, upregulation of the ANGPT2/TIE2+ M-MDSC signature in blood was associated with a poor prognosis. Our results identify the ANGPT2/TIE2+ M-MDSC axis as a participant in tumor immune evasion that should be taken into account in future cancer immunotherapy.

    更新日期:2020-01-23
  • Cross-talk between Colon Cells and Macrophages Increases ST6GALNAC1 and MUC1-sTn Expression in Ulcerative Colitis and Colitis-Associated Colon Cancer
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-22
    Michael Kvorjak; Yasmine Ahmed; Michelle L. Miller; Raahul Sriram; Claudia Coronnello; Jana G. Hashash; Douglas J. Hartman; Cheryl A. Telmer; Natasa Miskov-Zivanov; Olivera J. Finn; Sandra Cascio

    Patients with ulcerative colitis have an increased risk of developing colitis-associated colon cancer (CACC). Changes in glycosylation of the oncoprotein MUC1 commonly occur in chronic inflammation, including ulcerative colitis, and this abnormally glycosylated MUC1 promotes cancer development and progression. It is not known what causes changes in glycosylation of MUC1. Gene expression profiling of myeloid cells in inflamed and malignant colon tissues showed increased expression levels of inflammatory macrophage–associated cytokines compared with normal tissues. We analyzed the involvement of macrophage-associated cytokines in the induction of aberrant MUC1 glycoforms. A coculture system was used to examine the effects of M1 and M2 macrophages on glycosylation-related enzymes in colon cancer cells. M2-like macrophages induced the expression of the glycosyltransferase ST6GALNAC1, an enzyme that adds sialic acid to O-linked GalNAc residues, promoting the formation of tumor-associated sialyl-Tn (sTn) O-glycans. Immunostaining of ulcerative colitis and CACC tissue samples confirmed the elevated number of M2-like macrophages as well as high expression of ST6GALNAC1 and the altered MUC1-sTn glycoform on colon cells. Cytokine arrays and blocking antibody experiments indicated that the macrophage-dependent ST6GALNAC1 activation was mediated by IL13 and CCL17. We demonstrated that IL13 promoted phosphorylation of STAT6 to activate transcription of ST6GALNAC1. A computational model of signaling pathways was assembled and used to test IL13 inhibition as a possible therapy. Our findings revealed a novel cellular cross-talk between colon cells and macrophages within the inflamed and malignant colon that contributes to the pathogenesis of ulcerative colitis and CACC. See related Spotlight on p. 160

    更新日期:2020-01-23
  • MicroRNAs in Tumor Exosomes Drive Immune Escape in Melanoma
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-22
    Virginie Vignard; Maureen Labbé; Nadège Marec; Gwennan André-Grégoire; Nicolas Jouand; Jean-François Fonteneau; Nathalie Labarrière; Delphine Fradin

    MicroRNAs (miRNA), small noncoding RNAs that regulate gene expression, exist not only in cells but also in a variety of body fluids. These circulating miRNAs could enable intercellular communication. miRNAs are packaged in membrane-encapsulated vesicles, such as exosomes, or protected by RNA-binding proteins. Here, we report that miRNAs included in human melanoma exosomes regulate the tumor immune response. Using microscopy and flow cytometry, we demonstrate that CD8+ T cells internalize exosomes from different tumor types even if these cells do not internalize vesicles as readily as other immune cells. We explored the function of melanoma-derived exosomes in CD8+ T cells and showed that these exosomes downregulate T-cell responses through decreased T-cell receptor (TCR) signaling and diminished cytokine and granzyme B secretions. The result reduces the cells' cytotoxic activity. Using mimics, we found that miRNAs enriched in exosomes—such as Homo sapiens (hsa)-miR-3187-3p, hsa-miR-498, hsa-miR-122, hsa-miR149, and hsa-miR-181a/b—regulate TCR signaling and TNFα secretion. Our observations suggest that miRNAs in melanoma-derived exosomes aid tumor immune evasion and could be a therapeutic target.

    更新日期:2020-01-23
  • IL6 induces an IL22+ CD8+ T cell subset with potent antitumor function
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-21
    Michael St. Paul; Samuel D Saibil; Scott L Lien; SeongJun Han; Azin Sayad; David Mulder; Carlos R Garcia-Batres; Alisha R Elford; Kavita Israni-Winger; Céline Robert-Tissot; Michael Zon; Sarah R Katz; Patricia Shaw; Blaise A. Clarke; Marcus Q. Bernardini; Linh T. Nguyen; Benjamin Haibe-Kains; Trevor J Pugh; Pamela S. Ohashi

    CD8+ T cells can be polarized into several different subsets as defined by the cytokines they produce and the transcription factors that govern their differentiation. Here, we identified the polarizing conditions to induce an IL22 producing CD8+ Tc22 subset, which is dependent on IL6 and the aryl hydrocarbon receptor transcription factor. Further characterization showed that this subset was highly cytolytic and expresses a distinct cytokine profile and transcriptome relative to other subsets. In addition, polarized Tc22 were able to control tumor growth as well as, if not better than, the traditional IFN-γ producing Tc1 subset. Tc22s were also found to infiltrate the tumors of human ovarian cancer patients, comprising up to ~30% of expanded CD8+ tumor infiltrating lymphocytes (TIL). Importantly, IL22 production in these CD8+ TILs correlated with improved recurrence-free survival. Given the antitumor properties of Tc22 cells, it may be prudent to polarize T cells to the Tc22 lineage when using CAR-T or TCR transduction-based immunotherapies.

    更新日期:2020-01-22
  • Combined CD44- and CD25-targeted Near-Infrared Photoimmunotherapy Selectively Kills Cancer and Regulatory T cells in Syngeneic Mouse Cancer Models
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-17
    Yasuhiro Maruoka; Aki Furusawa; Ryuhei Okada; Fuyuki Inagaki; Daiki Fujimura; Hiroaki Wakiyama; Takuya Kato; Tadanobu Nagaya; Peter L. Choyke; Hisataka Kobayashi

    Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and selective cancer treatment that induces necrotic and immunogenic cell death and utilizes a monoclonal antibody conjugated to a photo-absorber dye, IR700DX, activated by NIR light. Although CD44 is surface cancer marker associated with drug resistance, anti-CD44-IR700 NIR-PIT results in inhibited cell growth and prolonged survival in multiple tumor types. Meanwhile, anti-CD25-IR700-targeted NIR-PIT has been reported to achieve selective and local depletion of FOXP3+CD25+CD4+ regulatory T cells (Tregs), which are primary immunosuppressive cells in the tumor microenvironment (TME), resulting in activation of local antitumor immunity. Combined NIR-PIT with CD44- and CD25-targeted agents has the potential to directly eliminate tumor cells and also amplify the immune response by removing FOXP3+CD25+CD4+ Tregs from the TME. We investigated the difference in therapeutic effects of CD44-targeted NIR-PIT alone, CD25-targeted NIR-PIT alone, and the combination of CD44- and CD25-targeted NIR-PIT in several syngeneic tumor models, including MC38-luc, LL/2, and MOC1. The combined NIR-PIT showed significant tumor growth inhibition and prolonged survival compared with CD44-targeted NIR-PIT alone in all tumor models and showed prolonged survival compared with CD25-targeted NIR-PIT alone in MC38-luc and LL/2 tumors. Combined CD44/CD25 NIR-PIT also resulted in some complete remissions, whereas this was not achieved with either type of NIR-PIT alone. Therefore, combined NIR-PIT simultaneously targeting cancer antigens and immunosuppressive cells in the TME may be more effective than either type of NIR-PIT alone and may have potential to induce prolonged immune responses in treated tumors.

    更新日期:2020-01-17
  • Glypican-3-specific CAR T cells co-expressing IL15 and IL21 have superior expansion and antitumor activity against hepatocellular carcinoma
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-17
    Sai Arun Batra; Purva Rathi; Linjie Guo; Amy N Courtney; Julien Fleurence; Julien Balzeau; Rahamthulla S Shaik; Thao P Nguyen; Meng-Fen Wu; Shaun Bulsara; Maksim Mamonkin; Leonid S Metelitsa; Andras Heczey

    Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death in the world and curative systemic therapies are lacking. Chimeric antigen receptor (CAR)-expressing T cells induce robust antitumor responses in patients with hematologic malignancies but have limited efficacy in patients with solid tumors including HCC. IL15 and IL21 promote T cell expansion, survival and function, and can improve the antitumor properties of T cells. We explored whether transgenic expression of IL15 and/or IL21 enhanced glypican-3-CAR (GPC3-CAR) T cells' antitumor properties against HCC. We previously optimized the co-stimulation in GPC3-CARs and selected a second generation GPC3-CAR incorporating a 4-1BB costimulatory endodomain (GBBz) for development. Here, we generated constructs encoding IL15, IL21, or both with GBBz (15.GBBz, 21.GBBz, and 21.15.GBBz, respectively) and examined the ability of transduced T cells to kill, produce effector cytokines, and expand in an antigen-dependent manner. We performed gene expression and phenotypic analyses of GPC3-CAR T cells and CRISPR-Cas9 knock-out of the TCF7 gene. Finally, we measured GPC3-CAR T cell antitumor activity in murine xenograft models of GPC3+ tumors.The increased proliferation of 21.15.GBBz T cells was at least in part dependent on upregulation and maintenance of TCF-1 (encoded by TCF7) and associated with a higher percentage of stem cell memory and central memory populations after manufacturing. T cells expressing 21.15.GBBz had superior in vitro and in vivo expansion and persistence, and the most robust antitumor activity in vivo. These results provided preclinical evidence to support the clinical evaluation of 21.15.GPC3-CAR T cells in patients with HCC.

    更新日期:2020-01-17
  • Matrix-targeting immunotherapy controls tumor growth and spread by switching macrophage phenotype
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-15
    Claire Deligne; Devadarssen Murdamoothoo; Anís N Gammage; Martha Gschwandtner; William Erne; Thomas Loustau; Anna M Marzeda; Raphael Carapito; Nicodème Paul; Inés Velázquez-Quesada; Imogen Mazzier; Zhen Sun; Gertraud Orend; Kim S Midwood

    The interplay between cancer cells and immune cells is a key determinant of tumor survival. Here, we uncovered how tumors exploit the immuno-modulatory properties of the extracellular matrix to create a microenvironment that enables their escape from immune surveillance. Using orthotopic grafting of mammary tumor cells in immunocompetent mice and autochthonous models of breast cancer, we discovered how tenascin-C, a matrix molecule absent from most healthy adult tissues but expressed at high levels and associated with poor patient prognosis in many solid cancers, controls the immune status of the tumor microenvironment. We found that, although host-derived tenascin-C promoted immunity via recruitment of pro-inflammatory, antitumoral macrophages, tumor-derived tenascin-C subverted host defense by polarizing tumor-associated macrophages towards a pathogenic, immune-suppressive phenotype. Therapeutic monoclonal antibodies that blocked tenascin-C activation of toll-like receptor 4 reversed this phenotypic switch in vitro and reduced tumor growth and lung metastasis in vivo, providing enhanced benefit in combination with anti-PD-L1 over either treatment alone. Combined tenascin-C:macrophage gene expression signatures delineated a significant survival benefit in people with breast cancer. These data revealed a new approach to targeting tumor-specific macrophage polarization that may be effective in controlling the growth and spread of breast tumors.

    更新日期:2020-01-15
  • CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-14
    Suresh de Silva; George Fromm; Casey W. Shuptrine; Kellsey Johannes; Arpita Patel; Kyung Jin Yoo; Kaiwen Huang; Taylor H. Schreiber

    Disrupting the binding of CD47 to SIRPα has emerged as a promising immunotherapeutic strategy for advanced cancers by potentiating antibody-dependent cellular phagocytosis (ADCP) of targeted antibodies. Preclinically, CD47/SIRPα blockade induces antitumor activity by increasing the phagocytosis of tumor cells by macrophages and enhancing the cross-presentation of tumor antigens to CD8+ T cells by dendritic cells; both of these processes are potentiated by CD40 signaling. Here we generated a novel, two-sided fusion protein incorporating the extracellular domains of SIRPα and CD40L, adjoined by a central Fc domain, termed SIRPα-Fc-CD40L. SIRPα-Fc-CD40L bound CD47 and CD40 with high affinity and activated CD40 signaling in the absence of Fc receptor cross-linking. No evidence of hemolysis, hemagglutination, or thrombocytopenia was observed in vitro or in cynomolgus macaques. Murine SIRPα-Fc-CD40L outperformed CD47 blocking and CD40 agonist antibodies in murine CT26 tumor models and synergized with immune checkpoint blockade of PD-1 and CTLA4. SIRPα-Fc-CD40L activated a type I interferon response in macrophages and potentiated the activity of ADCP-competent targeted antibodies both in vitro and in vivo. These data illustrated that whereas CD47/SIRPα inhibition could potentiate tumor cell phagocytosis, CD40-mediated activation of a type I interferon response provided a bridge between macrophage- and T-cell–mediated immunity that significantly enhanced durable tumor control and rejection.

    更新日期:2020-01-14
  • Intratumoral Plasmid IL12 Electroporation Therapy in Patients with Advanced Melanoma Induces Systemic and Intratumoral T-cell Responses
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-14
    Samantha K. Greaney; Alain P. Algazi; Katy K. Tsai; Kathryn T. Takamura; Lawrence Chen; Christopher G. Twitty; Li Zhang; Alan Paciorek; Robert H. Pierce; Mai H. Le; Adil I. Daud; Lawrence Fong

    Whereas systemic IL12 is associated with potentially life-threatening toxicity, intratumoral delivery of IL12 through tavokinogene telseplasmid electroporation (tavo) is safe and can induce tumor regression at distant sites. The mechanism by which these responses are mediated is unknown but is presumed to result from a cellular immune response. In a phase II clinical trial of tavo ([NCT01502293][1]), samples from 29 patients with cutaneous melanoma with in-transit disease were assessed for immune responses induced with this treatment. Within the blood circulating immune cell population, we found that the frequencies of circulating PD-1+ CD4+ and CD8+ T cells declined with treatment. Circulating immune responses to gp100 were also detected following treatment as measured by IFNγ ELISpot. Patients with a greater antigen-specific circulating immune response also had higher numbers of CD8+ T cells within the tumor. Clinical response was also associated with increased intratumoral CD3+ T cells. Finally, intratumoral T-cell clonality and convergence were increased after treatment, indicating a focusing of the T-cell receptor repertoire. These results indicated that local treatment with tavo can induce a systemic T-cell response and recruit T cells to the tumor microenvironment. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01502293&atom=%2Fcanimm%2Fearly%2F2020%2F01%2F13%2F2326-6066.CIR-19-0359.atom

    更新日期:2020-01-14
  • CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-14
    Hiroshi Kagamu; Shigehisa Kitano; Ou Yamaguchi; Kenichi Yoshimura; Katsuhisa Horimoto; Masashi Kitazawa; Kazuhiko Fukui; Ayako Shiono; Atsuhito Mouri; Fuyumi Nishihara; Yu Miura; Kosuke Hashimoto; Yoshitake Murayama; Kyoichi Kaira; Kunihiko Kobayashi

    Accumulating evidence indicates that CD8+ T cells in the tumor microenvironment and systemic CD4+ T-cell immunity play an important role in mediating durable antitumor responses. We longitudinally examined T-cell immunity in the peripheral blood of patients with non–small lung cancer and found that responders had significantly ( P < 0.0001) higher percentages of effector, CD62Llow CD4+ T cells prior to PD-1 blockade. Conversely, the percentage of CD25+FOXP3+ CD4+ T cells was significantly ( P = 0.034) higher in nonresponders. We developed a formula, which demonstrated 85.7% sensitivity and 100% specificity, based on the percentages of CD62Llow CD4+ T cells and CD25+FOXP3+ cells to predict nonresponders. Mass cytometry analysis revealed that the CD62Llow CD4+ T-cell subset expressed T-bet+, CD27−, FOXP3−, and CXCR3+, indicative of a Th1 subpopulation. CD62Llow CD4+ T cells significantly correlated with effector CD8+ T cells ( P = 0.0091) and with PD-1 expression on effector CD8+ T cells ( P = 0.0015). Gene expression analysis revealed that CCL19, CLEC-2A, IFNA, IL7, TGFBR3, CXCR3 , and HDAC9 were preferentially expressed in CD62Llow CD4+ T cells derived from responders. Notably, long-term responders, who had >500-day progression-free survival, showed significantly higher numbers of CD62Llow CD4+ T cells prior to PD-1 blockade therapy. Decreased CD62Llow CD4+ T-cell percentages after therapy resulted in acquired resistance, with long-term survivors maintaining high CD62Llow CD4+ T-cell percentages. These results pave the way for new treatment strategies for patients by monitoring CD4+ T-cell immune statuses in their peripheral blood.

    更新日期:2020-01-14
  • Lactic acidosis together with GM-CSF and M-CSF induces human macrophages toward an inflammatory pro-tumor phenotype
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-10
    Léa Paolini; Clément Adam; Céline Beauvillain; Laurence Preisser; Simon Blanchard; Pascale Pignon; Valérie Seegers; Louise-Marie Chevalier; Mario Campone; Romuald Wernert; Véronique Verriele; Pedro Raro; Norbert Ifrah; Vincent Lavoue; Philippe Descamps; Alain Morel; Veronique Catros; Guillaume Tcherkez; Guy Lenaers; Cinzia Bocca; Judith Kouassi Nzoughet; Vincent Procaccio; Yves Delneste; Pascale Jeannin

    In established tumors, tumor-associated macrophages (TAMs) orchestrate non-resolving cancer-related inflammation and produce mediators favoring tumor growth, metastasis and angiogenesis. However, the factors conferring inflammatory and pro-tumor properties on human macrophages remain largely unknown. Most solid tumors have high lactate content. We therefore analyzed the impact of lactate on human monocyte differentiation. We report that prolonged lactic acidosis induces the differentiation of monocytes into macrophages with a phenotype including pro-tumor and inflammatory characteristics. These cells produce tumor growth factors, inflammatory cytokines and chemokines as well as low amounts of IL10. These effects of lactate require its metabolism and are associated with HIF-1α stabilization. The expression of some lactate-induced genes is dependent on autocrine M-CSF consumption. Finally, TAMs with pro-tumor and inflammatory characteristics (VEGFhigh CXCL8+ IL1β+) are found in solid ovarian tumors. These results show that tumor-derived lactate links the pro-tumor features of TAMs with their inflammatory properties. Treatments that reduce tumor glycolysis or tumor-associated acidosis may help combat cancer.

    更新日期:2020-01-10
  • Aggressive Mammary Cancers Lacking Lymphocytic Infiltration Arise in Irradiated Mice and Can Be Prevented by Dietary Intervention
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-08
    Coral Omene; Lin Ma; Jade Moore; Haoxu Ouyang; Irineu Illa-Bochaca; William Chou; Manan S. Patel; Christopher Sebastiano; Sandra Demaria; Jian-Hua Mao; Kubra Karagoz; Michael L. Gatza; Mary Helen Barcellos-Hoff

    Because the incidence of breast cancer increases decades after ionizing radiation exposure, aging has been implicated in the evolution of the tumor microenvironment and tumor progression. Here, we investigated radiation-induced carcinogenesis using a model in which the mammary glands of 10-month-old BALB/c mice were transplanted with Trp53 -null mammary tissue 3 days after exposure to low doses of sparsely ionizing γ-radiation or densely ionizing particle radiation. Mammary transplants in aged, irradiated hosts gave rise to significantly more tumors that grew more rapidly than those in sham-irradiated mice, with the most pronounced effects seen in mice irradiated with densely ionizing particle radiation. Tumor transcriptomes identified a characteristic immune signature of these aggressive cancers. Consistent with this, fast-growing tumors exhibited an immunosuppressive tumor microenvironment with few infiltrating lymphocytes, abundant immunosuppressive myeloid cells, and high COX-2 and TGFβ. Only irradiated hosts gave rise to tumors lacking cytotoxic CD8+ lymphocytes (defined here as immune desert), which also occurred in younger irradiated hosts. These data suggest that host irradiation may promote immunosuppression. To test this, young chimera mice were fed chow containing a honeybee-derived compound with anti-inflammatory and immunomodulatory properties, caffeic acid phenethyl ester (CAPE). CAPE prevented the detrimental effects of host irradiation on tumor growth rate, immune signature, and immunosuppression. These data indicated that low-dose radiation, particularly densely ionizing exposure of aged mice, promoted more aggressive cancers by suppressing antitumor immunity. Dietary intervention with a nontoxic immunomodulatory agent could prevent systemic effects of radiation that fuel carcinogenesis, supporting the potential of this strategy for cancer prevention.

    更新日期:2020-01-08
  • Impact of TCR Diversity on the Development of Transplanted or Chemically Induced Tumors
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-07
    Karin Schreiber; Theodore G. Karrison; Steven P. Wolf; Kazuma Kiyotani; Madeline Steiner; Eric R. Littmann; Eric G. Pamer; Thomas Kammertoens; Hans Schreiber; Matthias Leisegang

    Burnet postulated that the diversity of T-cell receptors (TCR) allows T cells to protect against the development of cancers that display antigens with a similar, seemingly endless diversity. To test this hypothesis, we developed a strategy in which a single breeding pair of mice gives rise to four groups of sibling mice. Three of the four groups had a similar number of CD8+ T cells, but TCR diversity was either broad, significantly reduced, or absent when expressing only one type of TCR. The fourth group had no T cells. All mice shared the same housing, and, therefore, their microbial environment was similar. Only slight differences in the intestinal flora were observed under these conditions. An undisturbed broad TCR repertoire was required for the rejection of inoculated cancers displaying the natural antigenic heterogeneity of primary tumors, whereas even one type of TCR was sufficient to protect against artificial cancers stably expressing cognate antigens. The three groups of mice with limited or no TCR repertoire showed an increased risk of developing primary tumors after chemical induction. However, the risk of early death or morbidity in these cohorts of mice was significantly higher than in mice with a diverse TCR repertoire, and it remains unknown whether mice with reduced TCR diversity, who died early without cancer, would have developed tumors with higher, lower, or equal probability after induction. Together, TCR diversity seems crucial to overcome the natural genetic instability of cancers and their antigenic heterogeneity, which impacts the design of cellular therapies.

    更新日期:2020-01-07
  • pVACtools: a computational toolkit to identify and visualize cancer neoantigens
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-06
    Jasreet Hundal; Susanna Kiwala; Joshua McMichael; Christopher A Miller; Huiming Xia; Alexander T Wollam; Connor J Liu; Sidi Zhao; Yang-Yang Feng; Aaron P Graubert; Amber Z Wollam; Jonas Neichin; Megan Neveau; Jason Walker; William E Gillanders; Elaine R. Mardis; Obi L Griffith; Malachi Griffith

    Identification of neoantigens is a critical step in predicting response to checkpoint blockade therapy and design of personalized cancer vaccines. This is a cross-disciplinary challenge, involving genomics, proteomics, immunology, and computational approaches. We have built a computational framework called pVACtools that, when paired with a well-established genomics pipeline, produces an end-to-end solution for neoantigen characterization. pVACtools supports identification of altered peptides from different mechanisms including point mutations, in-frame or frameshift insertions and deletions, and gene fusions. Prediction of peptide:MHC binding is accomplished by supporting an ensemble of MHC Class I and II binding algorithms, within a framework designed to facilitate the incorporation of additional algorithms. Prioritization of predicted peptides occurs by integrating diverse data including mutant allele expression, peptide binding affinities, and determination whether a mutation is clonal or subclonal. Interactive visualization via a web interface allows clinical users to efficiently generate, review, and interpret results, selecting candidate peptides for individual patient vaccine designs. Additional modules support design choices needed for competing vaccine delivery approaches. One such module optimizes peptide ordering to minimize junctional epitopes in DNA-vector vaccines. Downstream analysis commands for synthetic long peptide vaccines are available to assess candidates for factors that influence peptide synthesis. All of the aforementioned steps are executed via a modular workflow consisting of tools for neoantigen prediction from somatic alterations (pVACseq and pVACfuse), prioritization, and selection using a graphical web-based interface (pVACviz), and design of DNA vector-based vaccines (pVACvector) and synthetic long peptide vaccines. pVACtools is available at pvactools.org.

    更新日期:2020-01-06
  • Self-Maintaining CD103+ Cancer-Specific T Cells Are Highly Energetic with Rapid Cytotoxic and Effector Responses
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-03
    Megat Abd Hamid; Huw Colin-York; Nasullah Khalid-Alham; Molly Browne; Lucia Cerundolo; Ji-Li Chen; Xuan Yao; Samara Rosendo-Machado; Craig Waugh; David Maldonado-Perez; Emma Bowes; Clare Verrill; Vincenzo Cerundolo; Christopher P. Conlon; Marco Fritzsche; Yanchun Peng; Tao Dong

    Enrichment of CD103+ tumor-infiltrating T lymphocytes (TIL) is associated with improved outcomes in patients. However, the characteristics of human CD103+ cytotoxic CD8+ T cells (CTL) and their role in tumor control remain unclear. We investigated the features and antitumor mechanisms of CD103+ CTLs by assessing T-cell receptor (TCR)–matched CD103+ and CD103– cancer-specific CTL immunity in vitro and its immunophenotype ex vivo . Interestingly, we found that differentiated CD103+ cancer-specific CTLs expressed the active form of TGFβ1 to continually self-regulate CD103 expression, without relying on external TGFβ1-producing cells. The presence of CD103 on CTLs improved TCR antigen sensitivity, which enabled faster cancer recognition and rapid antitumor cytotoxicity. These CD103+ CTLs had elevated energetic potential and faster migration capacity. However, they had increased inhibitory receptor coexpression and elevated T-cell apoptosis following prolonged cancer exposure. Our data provide fundamental insights into the properties of matured human CD103+ cancer-specific CTLs, which could have important implications for future designs of tissue-localized cancer immunotherapy strategies.

    更新日期:2020-01-04
  • A Sampling of Highlights from the Literature
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    American Association for Cancer Research

    ![][1] [ Fragmentation limits surveillance (from LunarSeaArt via Pixabay) ][2] Tumor-infiltrating natural killer (TINK) cells isolated from patients with liver cancer have fragmented mitochondria, less mitochondrial mass, higher ROS concentrations, and less electron transport chain

    更新日期:2020-01-02
  • Tumor Antigen Heterogeneity: The “Elephant in the Room” of Adoptive T-cell Therapy for Solid Tumors
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Steven M. Albelda

    A major hurdle to the efficacy of adoptive cell therapy and chimeric antigen receptors T-cell therapy is the choice of antigen(s) to target. An article in this issue addresses this by capitalizing on the synergistic effect of pathogen-based immunotherapy and adoptive cell therapy that results in epitope/antigen spreading and enhancement of the endogenous T-cell response against antigens not originally targeted. See article by Xin et al., [p. 7][1] [1]: /lookup/volpage/8/7?iss=1

    更新日期:2020-01-02
  • Translating Science into Survival: Report on the Fifth International Cancer Immunotherapy Conference
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Mustafa Diken; Oliver Kepp; Arthur N. Brodsky

    From September 25 to 28, 2019, in Paris, France, the Fifth International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research. This year, roughly 1,300 people attended the 4-day event, which covered the latest advances in cancer immunology and immunotherapy.

    更新日期:2020-01-02
  • Pathogen-Boosted Adoptive Cell Transfer Therapy Induces Endogenous Antitumor Immunity through Antigen Spreading
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Gang Xin; Achia Khatun; Paytsar Topchyan; Ryan Zander; Peter J. Volberding; Yao Chen; Jian Shen; Chunmei Fu; Aimin Jiang; William A. See; Weiguo Cui

    Loss of target antigens in tumor cells has become one of the major hurdles limiting the efficacy of adoptive cell therapy (ACT)–based immunotherapies. The optimal approach to overcome this challenge includes broadening the immune response from the initially targeted tumor-associated antigen (TAA) to other TAAs expressed in the tumor. To induce a more broadly targeted antitumor response, we utilized our previously developed Re-energized ACT (ReACT), which capitalizes on the synergistic effect of pathogen-based immunotherapy and ACT. In this study, we showed that ReACT induced a sufficient endogenous CD8+ T-cell response beyond the initial target to prevent the outgrowth of antigen loss variants in a B16-F10 melanoma model. Sequentially, selective depletion experiments revealed that Batf3-driven cDC1s were essential for the activation of endogenous tumor-specific CD8+ T cells. In ReACT-treated mice that eradicated tumors, we observed that endogenous CD8+ T cells differentiated into memory cells and facilitated the rejection of local and distal tumor rechallenge. By targeting one TAA with ReACT, we provided broader TAA coverage to counter antigen escape and generate a durable memory response against local relapse and metastasis. See related Spotlight on p. [2][1] [1]: /lookup/volpage/8/2?iss=1

    更新日期:2020-01-02
  • Tryptophan 2,3-Dioxygenase Expression Identified in Human Hepatocellular Carcinoma Cells and in Intratumoral Pericytes of Most Cancers
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Delia Hoffmann; Tereza Dvorakova; Vincent Stroobant; Caroline Bouzin; Aurélie Daumerie; Marie Solvay; Simon Klaessens; Marie-Claire Letellier; Jean-Christophe Renauld; Nicolas van Baren; Julie Lelotte; Etienne Marbaix; Benoit J. Van den Eynde

    Tryptophan catabolism is used by tumors to resist immune attack. It can be catalyzed by indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). IDO1 is frequently expressed in tumors and has been widely studied as a potential therapeutic target to reduce resistance to cancer immunotherapy. In contrast, TDO expression in tumors is not well characterized. Several human tumor cell lines constitutively express enzymatically active TDO. In human tumor samples, TDO expression has previously been detected by transcriptomics, but the lack of validated antibodies has precluded detection of the TDO protein and identification of TDO-expressing cells. Here, we developed novel TDO-specific monoclonal antibodies and confirmed by immunohistochemistry the expression of TDO in the majority of human cancers. In all hepatocarcinomas (10/10), TDO was expressed by most tumor cells. Some glioblastomas (10/39) and kidney carcinomas (1/10) also expressed TDO in tumor cells themselves but only in focal tumor areas. In addition, all cancers tested contained foci of nontumoral TDO-expressing cells, which were identified as pericytes by their expression of PDGFRβ and their location in vascular structures. These TDO-expressing pericytes belonged to morphologically abnormal tumor vessels and were found in high-grade tumors in the vicinity of necrotic or hemorrhagic areas, which were characterized by neoangiogenesis. We observed similar TDO-expressing pericytes in inflammatory pulmonary lesions containing granulation tissue, and in chorionic villi, two tissue types that also feature neoangiogenesis. Our results confirm TDO as a relevant immunotherapeutic target in hepatocellular carcinoma and suggest a proangiogenic role of TDO in other cancer types. See article by Schramme et al., [p. 32][1] [1]: /lookup/volpage/8/32?iss=1

    更新日期:2020-01-02
  • Inhibition of Tryptophan-Dioxygenase Activity Increases the Antitumor Efficacy of Immune Checkpoint Inhibitors
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Florence Schramme; Stefano Crosignani; Kim Frederix; Delia Hoffmann; Luc Pilotte; Vincent Stroobant; Julie Preillon; Gregory Driessens; Benoit J. Van den Eynde

    Tryptophan 2,3-dioxygenase (TDO) is an enzyme that degrades tryptophan into kynurenine and thereby induces immunosuppression. Like indoleamine 2,3-dioxygenase (IDO1), TDO is considered as a relevant drug target to improve the efficacy of cancer immunotherapy. However, its role in various immunotherapy settings has not been fully characterized. Here, we described a new small-molecule inhibitor of TDO that can modulate kynurenine and tryptophan in plasma, liver, and tumor tissue upon oral administration. We showed that this compound improved the ability of anti-CTLA4 to induce rejection of CT26 tumors expressing TDO. To better characterize TDO as a therapeutic target, we used TDO-KO mice and found that anti-CTLA4 or anti-PD1 induced rejection of MC38 tumors in TDO-KO, but not in wild-type mice. As MC38 tumors did not express TDO, we related this result to the high systemic tryptophan levels in TDO-KO mice, which lack the hepatic TDO needed to contain blood tryptophan. The antitumor effectiveness of anti-PD1 was abolished in TDO-KO mice fed on a tryptophan-low diet that normalized their blood tryptophan level. MC38 tumors expressed IDO1, which could have limited the efficacy of anti-PD1 in wild-type mice and could have been overcome in TDO-KO mice due to the high levels of tryptophan. Accordingly, treatment of mice with an IDO1 inhibitor improved the efficacy of anti-PD1 in wild-type, but not in TDO-KO, mice. These results support the clinical development of TDO inhibitors to increase the efficacy of immunotherapy of TDO-expressing tumors and suggest their effectiveness even in the absence of tumoral TDO expression. See article by Hoffmann et al., [p. 19][1] [1]: /lookup/volpage/8/19?iss=1

    更新日期:2020-01-02
  • A Neuropilin-1 Antagonist Exerts Antitumor Immunity by Inhibiting the Suppressive Function of Intratumoral Regulatory T Cells
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Keunok Jung; Jeong-Ah Kim; Ye-Jin Kim; Hyun Woo Lee; Chul-Ho Kim; Seokjin Haam; Yong-Sung Kim

    Regulatory T cells (Treg) are targeted for cancer immunotherapy because they suppress antitumor immunity. Although the importance of neuropilin-1 (NRP1) in the stability and function of intratumoral Tregs is well-documented, targeting of NRP1+ Tregs for anticancer immunotherapy has not been well explored. Here, we found that an NRP1 antagonist [Fc(AAG)-TPP11], generated by fusion of the NRP1-specific binding peptide TPP11 with the C-terminus of an effector function–deficient immunoglobulin Fc(AAG) variant, inhibits intratumoral NRP1+ Treg function and stability. Fc(AAG)-TPP11 triggered the internalization of NRP1, reducing its surface expression on Tregs and thereby inhibiting the suppressive function of Tregs. In two murine syngeneic tumor models, Fc(AAG)-TPP11 retarded tumor growth, comparable with a Treg-depleting anti–CTLA-4 antibody, without noticeable toxicity. Fc(AAG)-TPP11 inhibited NRP1-dependent Treg function, inducing unstable intratumoral Tregs, with reduced expression of Foxp3 and enhanced production of IFNγ, which subsequently increased the functionality and frequency of intratumoral CD8+ T cells. We also observed selective expression of NRP1 on Tregs isolated from human tumors, but not from the blood of healthy donors and patients with cancer, as well as ex vivo inhibition of intratumoral NRP1+ Treg function by Fc(AAG)-TPP11. Our results suggest that the NRP1 antagonist Fc(AAG)-TPP11 has therapeutic potential for the inhibition of intratumoral NRP1+ Tregs with limited unfavorable effects on peripheral Tregs.

    更新日期:2020-01-02
  • A High-Avidity T-cell Receptor Redirects Natural Killer T-cell Specificity and Outcompetes the Endogenous Invariant T-cell Receptor
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Elisa Landoni; Christof C. Smith; Giovanni Fucá; Yuhui Chen; Chuang Sun; Benjamin G. Vincent; Leonid S. Metelitsa; Gianpietro Dotti; Barbara Savoldo

    T-cell receptor (TCR) gene transfer redirects T cells to target intracellular antigens. However, the potential autoreactivity generated by TCR mispairing and occurrence of graft-versus-host disease in the allogenic setting due to the retention of native TCRs remain major concerns. Natural killer T cells (NKT) have shown promise as a platform for adoptive T-cell therapy in cancer patients. Here, we showed their utility for TCR gene transfer. We successfully engineered and expanded NKTs expressing a functional TCR (TCR NKTs), showing HLA-restricted antitumor activity in xenogeneic mouse models in the absence of graft-versus-mouse reactions. We found that TCR NKTs downregulated the invariant TCR (iTCR), leading to iTCR+TCR+ and iTCR−TCR+ populations. In-depth analyses of these subsets revealed that in iTCR−TCR+ NKTs, the iTCR, although expressed at the mRNA and protein levels, was retained in the cytoplasm. This effect resulted from a competition for binding to CD3 molecules for cell-surface expression by the transgenic TCR. Overall, our results highlight the feasibility and advantages of using NKTs for TCR expression for adoptive cell immunotherapies. NKT-low intrinsic alloreactivity that associated with the observed iTCR displacement by the engineered TCR represents ideal characteristics for “off-the-shelf” products without further TCR gene editing.

    更新日期:2020-01-02
  • Combined Vaccination with NY-ESO-1 Protein, Poly-ICLC, and Montanide Improves Humoral and Cellular Immune Responses in Patients with High-Risk Melanoma
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Anna Pavlick; Ana B. Blazquez; Marcia Meseck; Michael Lattanzi; Patrick A. Ott; Thomas U. Marron; Rose Marie Holman; John Mandeli; Andres M. Salazar; Christopher B. McClain; Gustavo Gimenez; Sreekumar Balan; Sacha Gnjatic; Rachel Lubong Sabado; Nina Bhardwaj

    Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results from early-phase clinical studies in patients with melanoma, NY-ESO-1 vaccine immunotherapy has not been widely investigated in larger trials; consequently, many questions remain as to the optimal vaccine formulation, predictive biomarkers, and sequencing and timing of vaccines in melanoma treatment. We conducted an adjuvant phase I/II clinical trial in high-risk resected melanoma to optimize the delivery of poly-ICLC, a TLR-3/MDA-5 agonist, as a component of vaccine formulation. A phase I dose-escalation part was undertaken to identify the MTD of poly-ICLC administered in combination with NY-ESO-1 and montanide. This was followed by a randomized phase II part investigating the MTD of poly-ICLC with NY-ESO-1 with or without montanide. The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events. Both regimens induced integrated NY-ESO-1–specific CD4+ T-cell and humoral responses. CD8+ T-cell responses were mainly detected in patients receiving montanide. T-cell avidity toward NY-ESO-1 peptides was higher in patients vaccinated with montanide. In conclusion, NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4+ T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8+ T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8+ T-cell responses to NY-ESO-1.

    更新日期:2020-01-02
  • XCL1/Glypican-3 Fusion Gene Immunization Generates Potent Antitumor Cellular Immunity and Enhances Anti–PD-1 Efficacy
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Kun Chen; Zhiyuan Wu; Hong Zhao; Yanmei Wang; Yutong Ge; Dongmei Wang; Zhengjiang Li; Changming An; Yuying Liu; Feifei Wang; Xinyu Bi; Hongying Wang; Jianqiang Cai; Chunhong Ma; Chunfeng Qu

    Cancer vaccines can amplify existing antitumor responses or prime naïve T cells to elicit effector T-cell functions in patients through immunization. Antigen-specific CD8+ T cells are crucial for the rejection of established tumors. We constructed XCL1-GPC3 fusion molecules as a liver cancer vaccine by linking the XCL1 chemokine to glypican-3 (GPC3), which is overexpressed in hepatocellular carcinoma (HCC). Cells expressing XCL1-GPC3 chemoattracted murine XCR1+CD8α+ dendritic cells (DC) and human XCR1+CD141+ DCs in vitro and promoted their IL12 production. After subcutaneous mXcl1-GPC3 plasmid injection, mXCL1-GPC3 was mainly detected in CD8α+ DCs of mouse draining lymph nodes. XCL1-GPC3–targeted DCs enhanced antigen-specific CD8+ T-cell proliferation and induced the de novo generation of GPC3-specific CD8+ T cells, which abolished GPC3-expressing tumor cells in mouse and human systems. We immunized a murine autochthonous liver cancer model, with a hepatitis B background, with the mXcl1-GPC3 plasmid starting at 6 weeks, when malignant hepatocyte clusters formed, or at 14 weeks, when liver tumor nodules developed, after diethylnitrosamine administration. mXcl1-GPC3 –immunized mice displayed significantly inhibited tumor formation and growth compared with GPC3 -immunized mice. After mXcl1-GPC3 immunization, mouse livers showed elevated production of IFNγ, granzyme B, IL18, CCL5, CXCL19, and Xcl1 and increased infiltration of GPC3-specific CD8+ T cells, activated natural killer (NK) cells, and NKT cells. The antitumor effects of these immune cells were further enhanced by the administration of anti–PD-1. Anti-HCC effects induced by hXCL1-GPC3 were confirmed in an HCC-PDX model from 3 patients. Thus, XCL1-GPC3 might be a promising cancer vaccine to compensate for the deficiency of the checkpoint blockades in HCC immunotherapy.

    更新日期:2020-01-02
  • Assessing the Magnitude of Immunogenic Cell Death Following Chemotherapy and Irradiation Reveals a New Strategy to Treat Pancreatic Cancer
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Jian Ye; Bradley N. Mills; Tony Zhao; Booyeon J. Han; Joseph D. Murphy; Ankit P. Patel; Carl J. Johnston; Edith M. Lord; Brian A. Belt; David C. Linehan; Scott A. Gerber

    Pancreatic ductal adenocarcinoma (PDAC) continues to have a dismal prognosis, in part, due to ineffective treatment strategies. The efficacy of some chemotherapies and especially radiotherapy is mediated partially by the immune system. Therefore, we hypothesized that profiling the immune response following chemotherapy and/or irradiation can be used as a readout for treatment efficacy but also to help identify optimal therapeutic schedules for PDAC. Using murine models of PDAC, we demonstrated that concurrent administration of stereotactic body radiotherapy (SBRT) and a modified dose of FOLFIRINOX (mFX) resulted in superior tumor control when compared with single or sequential treatment groups. Importantly, this combined treatment schedule enhanced the magnitude of immunogenic cell death, which in turn amplified tumor antigen presentation by dendritic cells and intratumoral CD8+ T-cell infiltration. Concurrent therapy also resulted in systemic immunity contributing to the control of established metastases. These findings provide a rationale for pursuing concurrent treatment schedules of SBRT with mFX in PDAC.

    更新日期:2020-01-02
  • Changes in CT Radiomic Features Associated with Lymphocyte Distribution Predict Overall Survival and Response to Immunotherapy in Non–Small Cell Lung Cancer
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Mohammadhadi Khorrami; Prateek Prasanna; Amit Gupta; Pradnya Patil; Priya D. Velu; Rajat Thawani; German Corredor; Mehdi Alilou; Kaustav Bera; Pingfu Fu; Michael Feldman; Vamsidhar Velcheti; Anant Madabhushi

    No predictive biomarkers can robustly identify patients with non–small cell lung cancer (NSCLC) who will benefit from immune checkpoint inhibitor (ICI) therapies. Here, in a machine learning setting, we compared changes (“delta”) in the radiomic texture (DelRADx) of CT patterns both within and outside tumor nodules before and after two to three cycles of ICI therapy. We found that DelRADx patterns could predict response to ICI therapy and overall survival (OS) for patients with NSCLC. We retrospectively analyzed data acquired from 139 patients with NSCLC at two institutions, who were divided into a discovery set (D1 = 50) and two independent validation sets (D2 = 62, D3 = 27). Intranodular and perinodular texture descriptors were extracted, and the relative differences were computed. A linear discriminant analysis (LDA) classifier was trained with 8 DelRADx features to predict RECIST-derived response. Association of delta-radiomic risk score (DRS) with OS was determined. The association of DelRADx features with tumor-infiltrating lymphocyte (TIL) density on the diagnostic biopsies ( n = 36) was also evaluated. The LDA classifier yielded an AUC of 0.88 ± 0.08 in distinguishing responders from nonresponders in D1, and 0.85 and 0.81 in D2 and D3. DRS was associated with OS [HR: 1.64; 95% confidence interval (CI), 1.22–2.21; P = 0.0011; C-index = 0.72). Peritumoral Gabor features were associated with the density of TILs on diagnostic biopsy samples. Our results show that DelRADx could be used to identify early functional responses in patients with NSCLC.

    更新日期:2020-01-02
  • IgA-Mediated Killing of Tumor Cells by Neutrophils Is Enhanced by CD47–SIRPα Checkpoint Inhibition
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Louise W. Treffers; Toine ten Broeke; Thies Rösner; J.H. Marco Jansen; Michel van Houdt; Steffen Kahle; Karin Schornagel; Paul J.J.H. Verkuijlen; Jan M. Prins; Katka Franke; Taco W. Kuijpers; Timo K. van den Berg; Thomas Valerius; Jeanette H.W. Leusen; Hanke L. Matlung

    Therapeutic monoclonal antibodies (mAb), directed toward either tumor antigens or inhibitory checkpoints on immune cells, are effective in cancer therapy. Increasing evidence suggests that the therapeutic efficacy of these tumor antigen–targeting mAbs is mediated—at least partially—by myeloid effector cells, which are controlled by the innate immune-checkpoint interaction between CD47 and SIRPα. We and others have previously demonstrated that inhibiting CD47–SIRPα interactions can substantially potentiate antibody-dependent cellular phagocytosis and cytotoxicity of tumor cells by IgG antibodies both in vivo and in vitro . IgA antibodies are superior in killing cancer cells by neutrophils compared with IgG antibodies with the same variable regions, but the impact of CD47–SIRPα on IgA-mediated killing has not been investigated. Here, we show that checkpoint inhibition of CD47–SIRPα interactions further enhances destruction of IgA antibody–opsonized cancer cells by human neutrophils. This was shown for multiple tumor types and IgA antibodies against different antigens, i.e., HER2/neu and EGFR. Consequently, combining IgA antibodies against HER2/neu or EGFR with SIRPα inhibition proved to be effective in eradicating cancer cells in vivo . In a syngeneic in vivo model, the eradication of cancer cells was predominantly mediated by granulocytes, which were actively recruited to the tumor site by SIRPα blockade. We conclude that IgA-mediated tumor cell destruction can be further enhanced by CD47–SIRPα checkpoint inhibition. These findings provide a basis for targeting CD47–SIRPα interactions in combination with IgA therapeutic antibodies to improve their potential clinical efficacy in tumor patients.

    更新日期:2020-01-02
  • Myeloid Cells Orchestrate Systemic Immunosuppression, Impairing the Efficacy of Immunotherapy against HPV+ Cancers
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Gabriele Galliverti; Stephan Wullschleger; Mélanie Tichet; Dhaarini Murugan; Nadine Zangger; Wesley Horton; Alan J. Korman; Lisa M. Coussens; Melody A. Swartz; Douglas Hanahan

    Cancers induced by human papillomaviruses (HPV) should be responsive to immunotherapy by virtue of expressing the immunogenic oncoproteins E6/E7. However, advanced forms of cervical cancer, driven by HPV, are poorly responsive to immune response–enhancing treatments involving therapeutic vaccination against these viral neoantigens. Leveraging a transgenic mouse model of HPV-derived cancers, K14HPV16/H2b, we demonstrated that a potent nanoparticle-based E7 vaccine, but not a conventional “liquid” vaccine, induced E7 tumor antigen–specific CD8+ T cells in cervical tumor–bearing mice. Vaccination alone or in combination with anti-PD-1/anti-CTLA4 did not elicit tumor regression nor increase CD8+ T cells in the tumor microenvironment (TME), suggesting the presence of immune-suppressive barriers. Patients with cervical cancer have poor dendritic cell functions, have weak cytotoxic lymphocyte responses, and demonstrate an accumulation of myeloid cells in the periphery. Here, we illustrated that myeloid cells in K14HPV16/H2b mice possess potent immunosuppressive activity toward antigen-presenting cells and CD8+ T cells, dampening antitumor immunity. These immune-inhibitory effects inhibited synergistic effects of combining our oncoprotein vaccine with immune checkpoint–blocking antibodies. Our data highlighted a link between HPV-induced cancers, systemic amplification of myeloid cells, and the detrimental effects of myeloid cells on CD8+ T-cell activation and recruitment into the TME. These results established immunosuppressive myeloid cells in lymphoid organs as an HPV+ cancer–induced means of circumventing tumor immunity that will require targeted abrogation to enable the induction of efficacious antitumor immune responses.

    更新日期:2020-01-02
  • TCR Repertoire Diversity of Peripheral PD-1+CD8+ T Cells Predicts Clinical Outcomes after Immunotherapy in Patients with Non–Small Cell Lung Cancer
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    Jiefei Han; Jianchun Duan; Hua Bai; Yuqi Wang; Rui Wan; Xin Wang; Si Chen; Yanhua Tian; Di Wang; Kailun Fei; Zhuoran Yao; Shuhang Wang; Zhimin Lu; Zhijie Wang; Jie Wang

    T-cell receptor (TCR)–based biomarkers might predict patient response to immune checkpoint blockade (ICB) but need further exploration and validation for that use. We sequenced complementarity-determining region 3 of TCRβ chains isolated from PD-1+ CD8+ T cells to investigate its value for predicting the response to anti–programmed cell death 1 (PD-1)/PD-ligand 1 (PD-L1) therapy in patients with non–small cell lung cancer (NSCLC). Two independent patient cohorts (cohort A, n = 25; cohort B, n = 15) were used as discovery and validation sets, respectively. Pre- and post-ICB peripheral blood samples were collected. In cohort A, patients with high PD-1+ CD8+ TCR diversity before ICB treatment showed better response to ICB and progression-free survival (PFS) compared with patients with low diversity [6.4 months vs. 2.5 months, HR, 0.39; 95% confidence interval (CI), 0.17–0.94; P = 0.021]. The results were validated in cohort B. Pre-ICB PD-1+ CD8+ TCR diversity achieved an optimal Youden's index of 0.81 (sensitivity = 0.87 and specificity = 0.94) for differentiating the ICB response in the merged dataset (cohort A plus cohort B). Patients with increased PD-1+ CD8+ TCR clonality after ICB treatment had longer PFS (7.3 months vs. 2.6 months, HR, 0.26; 95% CI, 0.08–0.86; P = 0.002) than those with decreased clonality. Thus, TCR diversity and clonality in peripheral blood PD-1+ CD8+ T cells may serve as noninvasive predictors of patient response to ICB and survival outcomes in NSCLC.

    更新日期:2020-01-02
  • Acknowledgment to Reviewers
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-01
    American Association for Cancer Research

    The Cancer Immunology Research editors wish to acknowledge with sincere appreciation the assistance of the following reviewers who have generously contributed their time and effort during the past year[1][1] in the appraisal of manuscripts. These reviewers have been enormously helpful in assessing

    更新日期:2020-01-02
  • Targeting CMTM6 Suppresses Stem Cell–Like Properties and Enhances Antitumor Immunity in Head and Neck Squamous Cell Carcinoma
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2020-01-02
    Lei Chen; Qi-Chao Yang; Yi-Cun Li; Lei-Lei Yang; Jian-Feng Liu; Hao Li; Yao Xiao; Lin-Lin Bu; Wen-Feng Zhang; Zhi-Jun Sun

    CMTM6, a regulator of PD-L1 expression, also modulates tumor immunity. Little is known about the function of CMTM6 and its mechanism of action in head and neck squamous cell carcinoma (HNSCC). In this study, we found by IHC analysis that CMTM6 overexpression predicted a poor prognosis for patients with HNSCC. We discovered that CMTM6 expression was correlated with increased activity through the Wnt/β-catenin signaling pathway, which is essential for tumorigenesis, maintenance of cancer stem cells (CSC), and the epithelial-to-mesenchymal transition (EMT) characteristic of multiple cancers. We used short hairpin RNA to eliminate expression of CMTM6, which led, in HNSCC cells, to reduced expression of nuclear β-catenin as well as inhibition of stem cell–like properties, TGFβ-induced EMT, and cell proliferation. Consistent with these results, we identified a significant positive correlation between expression of CMTM6 and EMT- and CSC-related genes in The Cancer Genome Atlas (TCGA). We found positive correlations for both RNA and protein between expression of CMTM6 and immune checkpoint components. CMTM6 silencing–induced PD-L1 downregulation delayed SCC7 tumor growth and increased CD8+ and CD4+ T-cell infiltration. The proportions of PD-1+, TIM-3+, VISTA+, LAG-3+, and B7-H3+ exhausted T cells were decreased significantly in the CMTM6 knockdown group. CMTM6 thus regulates stemness, EMT, and T-cell dysfunction and may be a promising therapeutic target in the treatment of HNSCC.

    更新日期:2020-01-02
  • Tumor cell-intrinsic USP22 suppresses antitumor immunity in pancreatic cancer
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-23
    Jinyang Li; Salina Yuan; Robert J Norgard; Fangxue Yan; Taiji Yamazoe; Andres Blanco; Ben Z. Stanger

    Although immune checkpoint blockade (ICB) improves clinical outcome in several types of malignancies, pancreatic ductal adenocarcinoma (PDA) remains refractory to this therapy. Preclinical studies have demonstrated that the relative abundance of suppressive myeloid cells vs. cytotoxic T cells determines the efficacy of combination immunotherapies, which include ICB. Here, we evaluated the role of the ubiquitin-specific protease 22 (USP22) as a regulator of the immune tumor microenvironment (TME) in PDA. We report that deletion of USP22 in pancreatic tumor cells reduced the infiltration of myeloid cells and promoted the infiltration of T cells and NK cells, leading to an improved response to combination immunotherapy. We also showed that ablation of tumor cell-intrinsic USP22 suppressed metastasis of pancreatic tumor cells in a T cell-dependent manner. Finally, we provide evidence that USP22 exerted its effects on the immune TME by reshaping the cancer cell transcriptome through its association with the deubiquitylase module of the SAGA/STAGA transcriptional co-activator complex. These results indicated that USP22 regulates immune infiltration and immunotherapy sensitivity in preclinical models of pancreatic cancer.

    更新日期:2019-12-23
  • High-throughput prediction of MHC class I and class II neoantigens with MHCnuggets
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-23
    Xiaoshan M Shao; Rohit Bhattacharya; Justin Huang; I.K. Ashok Sivakumar; Collin Tokheim; Lily Zheng; Dylan Hirsch; Benjamin Kaminow; Ashton Omdahl; Maria Bonsack; Angelika B Riemer; Victor E. Velculescu; Valsamo Anagnostou; Kymberleigh A Pagel; Rachel Karchin

    Computational prediction of binding between neoantigen peptides and major histocompatibility complex (MHC) proteins can be used to predict patient response to cancer immunotherapy. Current neoantigen predictors focus on in silico estimation of MHC binding affinity and are limited by low predictive value for actual peptide presentation, inadequate support for rare MHC alleles and poor scalability to high-throughput data sets. To address these limitations, we developed MHCnuggets, a deep neural network method that predicts peptide-MHC binding. MHCnuggets can predict binding for common or rare alleles of MHC class I or II with a single neural network architecture. Using a long short-term memory network (LSTM), MHCnuggets accepts peptides of variable length and is faster than other methods. When compared to methods that integrate binding affinity and MHC-bound peptide (HLAp) data from mass spectrometry, MHCnuggets yields a fourfold increase in positive predictive value on independent HLAp data. We applied MHCnuggets to 26 cancer types in TCGA, processing 26.3 million allele-peptide comparisons in under 2.3 hours, yielding 101,326 unique candidate immunogenic missense mutations (IMMs). Predicted IMM hotspots occurred in 38 genes, including 24 driver genes. Predicted IMM load was significantly associated with increased immune cell infiltration (P < 2 x 10-16) including CD8+ T cells. Only 0.16% of predicted immunogenic missense mutations were observed in more than two patients, with 61.7% of these derived from driver mutations. Thus, we describe a method for neoantigen prediction and its performance characteristics and demonstrate its utility in data sets representing multiple human cancers.

    更新日期:2019-12-23
  • A Sampling of Highlights from the Literature
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    American Association for Cancer Research

    ![][1] [ Helpful CD4s (by Ashlee Galloway, U.S. Dept. of Defense) ][2] Immunotherapy is beneficial to only a subset of patients for reasons not yet fully understood. A new predictive algorithm identifies MHC-II neoantigens important for induction of CD8+ T-cell antitumor responses.

    更新日期:2019-12-02
  • Location-Dependent B-cell Function in Glioblastoma
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Ferdinando Pucci

    Immunotherapy has shown remarkable successes in several tumor types and is now the first-line treatment for several conditions, including recurring disease. Nonetheless, a large fraction of patients does not respond, which is particularly true in glioblastoma. The results of Lee-Chang and colleagues point to intratumoral B cells as a potential target for immunotherapy. See article by Lee-Chang et al., [p. 1928][1] [1]: /lookup/volpage/7/1928?iss=12

    更新日期:2019-12-02
  • Phase II Trial of Ipilimumab with Stereotactic Radiation Therapy for Metastatic Disease: Outcomes, Toxicities, and Low-Dose Radiation–Related Abscopal Responses
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    James W. Welsh; Chad Tang; Patricia de Groot; Aung Naing; Kenneth R. Hess; John V. Heymach; Vassiliki A. Papadimitrakopoulou; Taylor R. Cushman; Vivek Subbiah; Joe Y. Chang; George R. Simon; Rishab Ramapriyan; Hampartsoum B. Barsoumian; Hari Menon; Maria Angelica Cortez; Erminia Massarelli; Quynh Nguyen; Padmanee Sharma; James P. Allison; Adi Diab; Vivek Verma; Uma Raju; Sherif G. Shaaban; Ramona Dadu; Maria E. Cabanillas; Kelvin Wang; Clark Anderson; Daniel R. Gomez; Stephen Hahn; Ritsuko Komaki; David S. Hong

    Ipilimumab is effective for patients with melanoma, but not for those with less immunogenic tumors. We report a phase II trial of ipilimumab with concurrent or sequential stereotactic ablative radiotherapy to metastatic lesions in the liver or lung ([NCT02239900][1]). Ipilimumab (every 3 weeks for 4 doses) was given with radiotherapy begun during the first dose (concurrent) or 1 week after the second dose (sequential) and delivered as 50 Gy in 4 fractions or 60 Gy in 10 fractions to metastatic liver or lung lesions. In total, 106 patients received ≥1 cycle of ipilimumab with radiation. Median follow-up was 10.5 months. Median progression-free survival time was 2.9 months (95% confidence interval, 2.45–3.40), and median overall survival time was not reached. Rates of clinical benefit of nonirradiated tumor volume were 26% overall, 28% for sequential versus 20% for concurrent therapy ( P = 0.250), and 31% for lung versus 14% for liver metastases ( P = 0.061). The sequential lung group had the highest rate of clinical benefit at 42%. There were no differences in treatment-related adverse events between groups. Exploratory analysis of nontargeted lesions revealed that lesions receiving low-dose radiation were more likely to respond than those that received no radiation (31% vs. 5%, P = 0.0091). This phase II trial of ipilimumab with stereotactic radiotherapy describes satisfactory outcomes and low toxicities, lending support to further investigation of combined-modality therapy for metastatic cancers. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02239900&atom=%2Fcanimm%2F7%2F12%2F1903.atom

    更新日期:2019-12-02
  • Tumor Vessel Normalization, Immunostimulatory Reprogramming, and Improved Survival in Glioblastoma with Combined Inhibition of PD-1, Angiopoietin-2, and VEGF
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Mariangela Di Tacchio; Jadranka Macas; Jakob Weissenberger; Kathleen Sommer; Oliver Bähr; Joachim P. Steinbach; Christian Senft; Volker Seifert; Martin Glas; Ulrich Herrlinger; Dietmar Krex; Matthias Meinhardt; Astrid Weyerbrock; Marco Timmer; Roland Goldbrunner; Martina Deckert; Andreas H. Scheel; Reinhard Büttner; Oliver M. Grauer; Jens Schittenhelm; Ghazaleh Tabatabai; Patrick N. Harter; Stefan Günther; Kavi Devraj; Karl H. Plate; Yvonne Reiss

    Glioblastoma (GBM) is a non-T-cell–inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.

    更新日期:2019-12-02
  • Myeloid-Derived Suppressive Cells Promote B cell–Mediated Immunosuppression via Transfer of PD-L1 in Glioblastoma
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Catalina Lee-Chang; Aida Rashidi; Jason Miska; Peng Zhang; Katarzyna C. Pituch; David Hou; Ting Xiao; Mariafausta Fischietti; Seong Jae Kang; Christina L. Appin; Craig Horbinski; Leonidas C. Platanias; Aurora Lopez-Rosas; Yu Han; Irina V. Balyasnikova; Maciej S. Lesniak

    The potent immunosuppression induced by glioblastoma (GBM) is one of the primary obstacles to finding effective immunotherapies. One hallmark of the GBM-associated immunosuppressive landscape is the massive infiltration of myeloid-derived suppressor cells (MDSC) and, to a lesser extent, regulatory T cells (Treg) within the tumor microenvironment. Here, we showed that regulatory B cells (Breg) are a prominent feature of the GBM microenvironment in both preclinical models and clinical samples. Forty percent of GBM patients ( n = 60) scored positive for B-cell tumor infiltration. Human and mouse GBM-associated Bregs were characterized by immunosuppressive activity toward activated CD8+ T cells, the overexpression of inhibitory molecules PD-L1 and CD155, and production of immunosuppressive cytokines TGFβ and IL10. Local delivery of B cell–depleting anti-CD20 immunotherapy improved overall survival of animals (IgG vs. anti-CD20 mean survival: 18.5 vs. 33 days, P = 0.0001), suggesting a potential role of Bregs in GBM progression. We unveiled that GBM-associated MDSCs promoted regulatory B-cell function by delivering microvesicles transporting membrane-bound PD-L1, able to be up-taken by tumoral B cells. The transfer of functional PD-L1 via microvesicles conferred Bregs the potential to suppress CD8+ T-cell activation and acquisition of an effector phenotype. This work uncovered the role of B cells in GBM physiopathology and provides a mechanism by which the GBM microenvironment controls B cell–mediated immunosuppression. See related Spotlight on [p. 1902][1] [1]: /lookup/volpage/7/1902?iss=12

    更新日期:2019-12-02
  • IL6 Modulates the Immune Status of the Tumor Microenvironment to Facilitate Metastatic Colonization of Colorectal Cancer Cells
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Yujiro Toyoshima; Hidemitsu Kitamura; Huihui Xiang; Yosuke Ohno; Shigenori Homma; Hideki Kawamura; Norihiko Takahashi; Toshiya Kamiyama; Mishie Tanino; Akinobu Taketomi

    It is unknown as to how liver metastases are correlated with host immune status in colorectal cancer. In this study, we found that IL6, a proinflammatory cytokine produced in tumor-bearing states, promoted the metastatic colonization of colon cancer cells in association with dysfunctional antitumor immunity. In IL6-deficient mice, metastatic colonization of CT26 cells in the liver was reduced, and the antitumor effector function of CD8+ T cells, as well as IL12 production by CD11c+ dendritic cells, were augmented in vivo . IL6-deficient mice exhibited enhanced IFN-AR1–mediated type I interferon signaling, which upregulated PD-L1 and MHC class I expression on CT26 cells. In vivo injection of anti–PD-L1 effectively suppressed the metastatic colonization of CT26 cells in Il6 −/− but not in Il6 +/+ mice. Finally, we confirmed that colorectal cancer patients with low IL6 expression in their primary tumors showed prolonged disease-free survival. These findings suggest that IL6 may be a promising target for the treatment of metastasis in colorectal cancers by improving host immunity.

    更新日期:2019-12-02
  • Trifluridine/Tipiracil plus Oxaliplatin Improves PD-1 Blockade in Colorectal Cancer by Inducing Immunogenic Cell Death and Depleting Macrophages
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Emeric Limagne; Marion Thibaudin; Lisa Nuttin; Aodrenn Spill; Valentin Derangère; Jean-David Fumet; Nadia Amellal; Elisa Peranzoni; Valérie Cattan; François Ghiringhelli

    Trifluridine/tipiracil (FTD/TPI) is a new antimetabolite agent used to treat chemorefractory metastatic colorectal cancer. FTD/TPI induced immunogenic cell death (ICD) in vitro in the microsatellite-stable (MSS) CT26 mouse colon carcinoma cell line, as well as in various human MSS colorectal cancer cell lines (SW620, Caco-2, and Colo-320). The combination of FTD/TPI with oxaliplatin synergized to promote ICD. In vivo , the combination was able to induce ICD, but not the single agents, although all treatment groups showed T-cell dependency. In addition, FTD/TPI and oxaliplatin did not affect regulatory T cells or myeloid-derived suppressor cells but eliminated type-2 tumor-associated macrophages (TAM2), resulting in higher cytotoxic CD8+ T-cell infiltration and activation. This effect was concomitantly associated with PD-L1 expression on tumor cells and PD-1 induction on CD8+ T cells, leading to secondary T-cell exhaustion. Finally, although anti–PD-1 was unable to synergize with FTD/TPI or oxaliplatin monotherapy, concomitant administration of anti–PD-1 to FTD/TPI and oxaliplatin enhanced the antitumor efficacy of the double chemotherapy. Our study showed a novel immunomodulatory role of FTD/TPI and oxaliplatin in depleting TAM2. The combination of oxaliplatin and FTD/TPI induced ICD in vivo, providing a rationale for the use of these drugs to eliminate immunosuppressive cells and boost checkpoint efficacy in patients with metastatic colorectal cancer.

    更新日期:2019-12-02
  • MicroRNAs Affect Complement Regulator Expression and Mitochondrial Activity to Modulate Cell Resistance to Complement-Dependent Cytotoxicity
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Yaron Hillman; Mariya Mardamshina; Metsada Pasmanik-Chor; Lea Ziporen; Tamar Geiger; Noam Shomron; Zvi Fishelson

    MicroRNAs (miR) are small RNA molecules that shape the cell transcriptome and proteome through regulation of mRNA stability and translation. Here, we examined their function as determinants of cell resistance to complement-dependent cytotoxicity (CDC). To achieve this goal, we compared the expression of microRNAs between complement-resistant and -sensitive K562 leukemia, Raji lymphoma, and HCT-116 colorectal carcinoma cells. Global microRNA array analysis identified miR-150, miR-328, and miR-616 as regulators of CDC resistance. Inhibition of miR-150 reduced resistance, whereas inhibition of miR-328 or miR-616 enhanced cell resistance. Treatment of K562 cells with a sublytic dose of complement was shown to rapidly increase miR-150, miR-328, and miR-616 expression. Protein targets of these microRNAs were analyzed in K562 cells by mass spectrometry–based proteomics. Expression of the complement membrane regulatory proteins CD46 and CD59 was significantly enhanced after inhibition of miR-328 and miR-616. Enrichment of proteins of mitochondria, known target organelles in CDC, was observed after miR-150, miR-328, and miR-616 inhibition. In conclusion, miR-150, miR-328, and miR-616 regulate cell resistance to CDC by modifying the expression of the membrane complement regulators CD46 and CD59 and the response of the mitochondria to complement lytic attack. These microRNAs may be considered targets for intervention in complement-associated diseases and in anticancer, complement-based therapy.

    更新日期:2019-12-02
  • ALK and RET Inhibitors Promote HLA Class I Antigen Presentation and Unmask New Antigens within the Tumor Immunopeptidome
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Claire Y. Oh; Martin G. Klatt; Christopher Bourne; Tao Dao; Megan M. Dacek; Elliott J. Brea; Sung Soo Mun; Aaron Y. Chang; Tatyana Korontsvit; David A. Scheinberg

    T-cell immunotherapies are often thwarted by the limited presentation of tumor-specific antigens abetted by the downregulation of human leukocyte antigen (HLA). We showed that drugs inhibiting ALK and RET produced dose-related increases in cell-surface HLA in tumor cells bearing these mutated kinases in vitro and in vivo , as well as elevated transcript and protein expression of HLA and other antigen-processing machinery. Subsequent analysis of HLA-presented peptides after ALK and RET inhibitor treatment identified large changes in the immunopeptidome with the appearance of hundreds of new antigens, including T-cell epitopes associated with impaired peptide processing (TEIPP) peptides. ALK inhibition additionally decreased PD-L1 levels by 75%. Therefore, these oncogenes may enhance cancer formation by allowing tumors to evade the immune system by downregulating HLA expression. Altogether, RET and ALK inhibitors could enhance T-cell–based immunotherapies by upregulating HLA, decreasing checkpoint blockade ligands, and revealing new, immunogenic, cancer-associated antigens.

    更新日期:2019-12-02
  • Tumor-Specific Regulatory T Cells from the Bone Marrow Orchestrate Antitumor Immunity in Breast Cancer
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Yingzi Ge; Hans-Henning Böhm; Anchana Rathinasamy; Maria Xydia; Xiaoying Hu; Mudita Pincha; Ludmila Umansky; Christopher Breyer; Michael Hillier; Andreas Bonertz; Alexandra Sevko; Christoph Domschke; Florian Schuetz; Helge Frebel; Steffen Dettling; Christel Herold-Mende; Christoph Reissfelder; Jürgen Weitz; Viktor Umansky; Philipp Beckhove

    Endogenous antitumor effector T-cell responses and immune-suppressive regulatory T cells (Treg) critically influence the prognosis of patients with cancer, yet many of the mechanisms of how this occurs remain unresolved. On the basis of an analysis of the function, antigen specificity, and distribution of tumor antigen–reactive T cells and Tregs in patients with breast cancer and transgenic mouse tumor models, we showed that tumor-specific Tregs were selectively activated in the bone marrow (BM) and egressed into the peripheral blood. The BM was constantly depleted of tumor-specific Tregs and was instead a site of increased induction and activity of tumor-reactive effector/memory T cells. Treg egress from the BM was associated with activation-induced expression of peripheral homing receptors such as CCR2. Because breast cancer tissues express the CCR2 ligand CCL2, the activation and egress of tumor antigen–specific Tregs in the BM resulted in the accumulation of Tregs in breast tumor tissue. Such immune compartmentalization and redistribution of T-cell subpopulations between the BM and peripheral tissues were achieved by vaccination with adenoviral vector–encoded TRP-2 tumor antigen in a RET transgenic mouse model of spontaneous malignant melanoma. Thus, the BM simultaneously represented a source of tumor-infiltrating Tregs and a site for the induction of endogenous tumor-specific effector T-cell responses, suggesting that both antitumor immunity and local immune suppression are orchestrated in the BM.

    更新日期:2019-12-02
  • Silencing Fc Domains in T cell–Engaging Bispecific Antibodies Improves T-cell Trafficking and Antitumor Potency
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Linlin Wang; Sayed Shahabuddin Hoseini; Hong Xu; Vladimir Ponomarev; Nai-Kong Cheung

    Bispecific antibodies (BsAb) that engage T cells bind to tumor cells via a tumor-associated antigen and to T cells through surface CD3. BsAbs have promising antitumor properties in vivo . Here, we describe the effects of Fc silencing on BsAb-driven T-cell trafficking to solid tumors. We used BsAbs specific for disialoganglioside GD2 or oncoprotein ErbB2 (HER2) and built on the IgG(L)-scFv platform with or without Fc silencing. We studied the kinetics of T-cell infiltration from blood into solid tumor masses when driven by these BsAbs. We also investigated the therapeutic efficacy of these BsAbs in two mouse models: immunodeficient mice xenografted with patient-derived GD2+ neuroblastoma or HER2+ breast cancer, and human CD3ε transgenic mice implanted with a GD2+ murine tumor. BsAbs built with intact Fc domain were unable to drive T cells to tumor, thereby failing to achieve an antitumor effect in mice. T cells became sequestered in lungs by myeloid cells or depleted in circulation. In contrast, when Fc function was silenced by N297A ± K322A mutations, T cells were able to infiltrate into subcutaneous solid tumors, a prerequisite for successful therapy outcome.

    更新日期:2019-12-02
  • T-cell Receptors Engineered De Novo for Peptide Specificity Can Mediate Optimal T-cell Activity without Self Cross-Reactivity
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Preeti Sharma; Daniel T. Harris; Jennifer D. Stone; David M. Kranz

    Despite progress in adoptive T-cell therapies, the identification of targets remains a challenge. Although chimeric antigen receptors recognize cell-surface antigens, T-cell receptors (TCR) have the advantage that they can target the array of intracellular proteins by binding to peptides associated with major histocompatibility complex (MHC) products (pepMHC). Although hundreds of cancer-associated peptides have been reported, it remains difficult to identify effective TCRs against each pepMHC complex. Conventional approaches require isolation of antigen-specific CD8+ T cells, followed by TCRαβ gene isolation and validation. To bypass this process, we used directed evolution to engineer TCRs with desired peptide specificity. Here, we compared the activity and cross-reactivity of two affinity-matured TCRs (T1 and RD1) with distinct origins. T1-TCR was isolated from a melanoma-reactive T-cell line specific for MART-1/HLA-A2, whereas RD1-TCR was derived de novo against MART-1/HLA-A2 by in vitro engineering. Despite their distinct origins, both TCRs exhibited similar peptide fine specificities, focused on the center of the MART-1 peptide. In CD4+ T cells, both TCRs mediated activity against MART-1 presented by HLA-A2. However, in CD8+ T cells, T1, but not RD1, demonstrated cross-reactivity with endogenous peptide/HLA-A2 complexes. Based on the fine specificity of these and other MART-1 binding TCRs, we conducted bioinformatics scans to identify structurally similar self-peptides in the human proteome. We showed that the T1-TCR cross-reacted with many of these self-peptides, whereas the RD1-TCR was rarely cross-reactive. Thus, TCRs such as RD1, generated de novo against cancer antigens, can serve as an alternative to TCRs generated from T-cell clones.

    更新日期:2019-12-02
  • Trabectedin Reveals a Strategy of Immunomodulation in Chronic Lymphocytic Leukemia
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Priyanka Banerjee; Ronghua Zhang; Cristina Ivan; Giovanni Galletti; Karen Clise-Dwyer; Federica Barbaglio; Lydia Scarfò; Miguel Aracil; Christian Klein; William Wierda; William Plunkett; Federico Caligaris-Cappio; Varsha Gandhi; Michael J. Keating; Maria Teresa S. Bertilaccio

    Chronic lymphocytic leukemia (CLL) is a B-cell neoplasia characterized by protumor immune dysregulation involving nonmalignant cells of the microenvironment, including T lymphocytes and tumor-associated myeloid cells. Although therapeutic agents have improved treatment options for CLL, many patients still fail to respond. Some patients also show immunosuppression. We have investigated trabectedin, a marine-derived compound with cytotoxic activity on macrophages in solid tumors. Here, we demonstrate that trabectedin induces apoptosis of human primary leukemic cells and also selected myeloid and lymphoid immunosuppressive cells, mainly through the TRAIL/TNF pathway. Trabectedin modulates transcription and translation of IL6, CCL2, and IFNα in myeloid cells and FOXP3 in regulatory T cells. Human memory CD8+ T cells downregulate PD-1 and, along with monocytes, exert in vivo antitumor function. In xenograft and immunocompetent CLL mouse models, trabectedin has antileukemic effects and antitumor impact on the myeloid and lymphoid cells compartment. It depletes myeloid-derived suppressor cells and tumor-associated macrophages and increases memory T cells. Trabectedin also blocks the PD-1/PD-L1 axis by targeting PD-L1+ CLL cells, PD-L1+ monocytes/macrophages, and PD-1+ T cells. Thus, trabectedin behaves as an immunomodulatory drug with potentially attractive therapeutic value in the subversion of the protumor microenvironment and in overcoming chemoimmune resistance.

    更新日期:2019-12-02
  • Mammary Tumor Cells with High Metastatic Potential Are Hypersensitive to Macrophage-Derived HGF
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Takanori Kitamura; Yu Kato; Demi Brownlie; Daniel Y.H. Soong; Gaël Sugano; Nicolle Kippen; Jiufeng Li; Dahlia Doughty-Shenton; Neil Carragher; Jeffrey W. Pollard

    Metastasis-associated macrophages (MAM) promote persistent growth of breast cancer cells at the metastatic site and are, thus, an attractive therapeutic target to treat breast cancer metastasis, a leading cause of cancer-related death in women. However, the precise mechanisms behind MAM-mediated metastatic tumor outgrowth have not been fully elucidated. Using mouse models of metastatic breast cancer, we showed that MAMs uniquely expressed hepatocyte growth factor (HGF) in metastatic tumors. We also demonstrated that a selected population of cancer cells with high metastatic potential (cancer cells that can establish metastatic tumors in mice with higher number and incidence than parental cells) had higher expression of HGF receptor, MNNG HOS transforming gene (MET), and were more responsive to HGF released from macrophages compared with the parental cells. Blockade of MET signaling in cancer cells suppressed metastatic tumor expansion, in part, through activation of natural killer cells. Results from this study suggest an approach to prevent life-threatening metastatic tumor formation using blockade of MAM-induced MET signal activation in metastatic cancer cells.

    更新日期:2019-12-02
  • Tumor Immune Microenvironment and Chemosensitivity Signature for Predicting Response to Chemotherapy in Gastric Cancer
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-12-01
    Yuming Jiang; Jingjing Xie; Weicai Huang; Hao Chen; Sujuan Xi; Zhen Han; Lei Huang; Tian Lin; Li-Ying Zhao; Yan-Feng Hu; Jiang Yu; Shi-Rong Cai; Tuanjie Li; Guoxin Li

    Current gastric cancer staging alone cannot predict prognosis and adjuvant chemotherapy benefits in stage II and III gastric cancer. Tumor immune microenvironment biomarkers and tumor-cell chemosensitivity might add predictive value to staging. This study aimed to construct a predictive signature integrating tumor immune microenvironment and chemosensitivity-related features to improve the prediction of survival and adjuvant chemotherapy benefits in patients with stage II to III gastric cancer. We used IHC to assess 26 features related to tumor, stroma, and chemosensitivity in tumors from 223 patients and evaluated the association of the features with disease-free survival (DFS) and overall survival (OS). Support vector machine (SVM)–based methods were used to develop the predictive signature, which we call the SVM signature. Validation of the signature was performed in two independent cohorts of 445 patients. The diagnostic signature integrated seven features: CD3+ cells at the invasive margin (CD3 IM), CD8+ cells at the IM (CD8 IM), CD45RO+ cells in the center of tumors (CD45RO CT), CD66b+ cells at the IM (CD66b IM), CD34+ cells, periostin, and cyclooxygenase-2. Patients fell into low- and high-SVM groups with significant differences in 5-year DFS and OS in the training and validation cohorts (all P < 0.001). The signature was an independent prognosis indicator in multivariate analysis in each cohort. The signature had better prognostic value than various clinicopathologic risk factors and single features. High-SVM patients exhibited a favorable response to adjuvant chemotherapy. Thus, this SVM signature predicted survival and has the potential for identifying patients with stage II and III gastric cancer who could benefit from adjuvant chemotherapy.

    更新日期:2019-12-02
  • Self-maintaining CD103+ cancer-specific T cells are highly energetic with rapid cytotoxic and effector responses
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-26
    Megat Abd Hamid; Huw Colin-York; Nasullah Khalid-Alham; Molly Browne; Lucia Cerundolo; Ji-Li Chen; Xuan Yao; Samara Rosendo-Machado; Craig Waugh; David Maldonado-Perez; Emma Bowes; Clare Verrill; Vincenzo Cerundolo; Christopher P Conlon; Marco Fritzsche; Yanchun Peng; Tao Dong

    Enrichment of CD103+ tumor-infiltrating T lymphocytes (TILs) is associated with improved outcomes in patients. However, the characteristics of human CD103+ cytotoxic CD8+ T cells (CTLs) and their role in tumor control remains unclear. We investigated the features and antitumor mechanisms of CD103+ CTLs by assessing T-cell receptor (TCR)-matched CD103+ and CD103- cancer-specific CTL immunity in vitro and its immunophenotype ex vivo. Interestingly, we found that differentiated CD103+ cancer-specific CTLs expressed the active form of TGFβ1 to continually self-regulate CD103 expression, without relying on external TGFβ1-producing cells. The presence of CD103 on CTLs improved TCR antigen sensitivity which enabled faster cancer recognition and rapid antitumor cytotoxicity. These CD103+ CTLs had elevated energetic potential and faster migration capacity. However, they had increased inhibitory receptor co-expression and elevated T-cell apoptosis following prolonged cancer exposure. Our data provide fundamental insights into the properties of matured human CD103+ cancer-specific CTLs, which could have important implications for future designs of tissue-localized cancer immunotherapy strategies.

    更新日期:2019-11-27
  • A Sampling of Highlights from the Literature
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    American Association for Cancer Research

    ![][1] [ Inflammation-triggered breast metastasis (by the National Cancer Institute via Wikimedia Commons) ][2] Systemic inflammation foreshadows poor prognoses for patients with cancer. An analysis of 16 different murine breast cancer models, and heterogeneous clinical breast tumor

    更新日期:2019-11-01
  • Harnessing Natural Killer Cell Antitumor Immunity: From the Bench to Bedside
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    Karrune V. Woan; Jeffrey S. Miller

    Natural killer (NK) cells are critical effector lymphocytes mediating tumor immune surveillance and clearance. They do so by direct tumor killing using cytolytic granules and death receptors, and by interfacing with and potentiating adaptive immune responses through the production of cytokines. From a therapeutic perspective, NK cells have been shown to exert graft-versus-leukemia activity in the context of hematopoietic stem cell transplantation and are important in the clinical efficacy of antibodies. Advances in basic and translational NK cell biology have led to multiple potential strategies to augment their in vivo activity to improve antitumor responses. Despite their potent effects, NK cells have been shown to be safe for adoptive cell therapy in both the autologous and allogeneic settings, with promising, but so far limited, clinical efficacy. This review will provide an overview of strategies being pursued to improve NK cell activity and efficacy, focusing on cell source, NK cell activation, and in vivo persistence.

    更新日期:2019-11-01
  • Direct Detection and Quantification of Neoantigens
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    Qing Wang; Jacqueline Douglass; Michael S. Hwang; Emily Han-Chung Hsiue; Brian J. Mog; Ming Zhang; Nickolas Papadopoulos; Kenneth W. Kinzler; Shibin Zhou; Bert Vogelstein

    Many immunotherapeutic approaches under development rely on T-cell recognition of cancer-derived peptides bound to human leukocyte antigen molecules on the cell surface. Direct experimental demonstration that such peptides are processed and bound is currently challenging. Here, we describe a method that meets this challenge. The method entailed an optimized immunoprecipitation protocol coupled with two-dimensional chromatography and mass spectrometry. The ability to detect and quantify minute amounts of predefined antigens should be useful both for basic research in tumor immunology and for the development of rationally designed cancer vaccines.

    更新日期:2019-11-01
  • Anti–PD-1–Induced Pneumonitis Is Associated with Persistent Imaging Abnormalities in Melanoma Patients
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    Douglas B. Johnson; Kevin B. Taylor; Justine V. Cohen; Noura Ayoubi; Alexandra M. Haugh; Daniel Y. Wang; Brian D. Schlick; Amber L. Voorhees; Kenneth L. Gage; Florian J. Fintelmann; Ryan J. Sullivan; Zeynep Eroglu; Richard G. Abramson

    Pneumonitis may complicate anti-programmed death-1 (PD-1) therapy, although symptoms usually resolve with steroids. The long-term effects on respiratory function, however, are not well defined. We screened melanoma patients treated with anti–PD-1, with and without ipilimumab (anti–CTLA-4), and identified 31 patients with pneumonitis. Median time to radiographic findings was 4.8 months. Twenty-three patients (74%) presented with respiratory symptoms, whereas 8 (26%) were asymptomatic, and 11 (35%) were hospitalized. With 22.1 months median follow-up, 27 patients (87%) had resolution of symptoms, whereas 4 had persistent cough, dyspnea, and/or wheezing. By contrast, the rate of radiographic resolution was lower: Only 11 (35%) had complete radiographic resolution, whereas 14 (45%) had improvement of pneumonitis with persistent scarring or opacities, and 6 (19%) had persistent or worsened ground-glass opacities and/or nodular densities. Persistence (vs. resolution) of radiographic findings was associated with older age and initial need for steroids but not with need for hospitalization, timing of onset, or treatment regimen (combination vs. monotherapy). Among patients with serial pulmonary function tests, lung function improved with time. Although symptoms of anti–PD-1–induced pneumonitis resolved quickly, scarring or inflammation frequently persisted on computerized tomography. Therefore, further study of subclinical pulmonary effects of anti–PD-1 is needed.

    更新日期:2019-11-01
  • Head and Neck Cancers Promote an Inflammatory Transcriptome through Coactivation of Classic and Alternative NF-κB Pathways
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    Xinping Yang; Hui Cheng; Jianhong Chen; Ru Wang; Anthony Saleh; Han Si; Steven Lee; Emine Guven-Maiorov; Ozlem Keskin; Attila Gursoy; Ruth Nussinov; Jugao Fang; Carter Van Waes; Zhong Chen

    Head and neck squamous cell carcinomas (HNSCC) promote inflammation in the tumor microenvironment through aberrant NF-κB activation, but the genomic alterations and pathway networks that modulate NF-κB signaling have not been fully dissected. Here, we analyzed genome and transcriptome alterations of 279 HNSCC specimens from The Cancer Genome Atlas (TCGA) cohort and identified 61 genes involved in NF-κB and inflammatory pathways. The top 30 altered genes were distributed across 96% of HNSCC samples, and their expression was often correlated with genomic copy-number alterations (CNA). Ten of the amplified genes were associated with human papilloma virus (HPV) status. We sequenced 15 HPV− and 11 HPV+ human HNSCC cell lines, and three oral mucosa keratinocyte lines, and supervised clustering revealed that 28 of 61 genes exhibit altered expression patterns concordant with HNSCC tissues and distinct signatures related to their HPV status. RNAi screening using an NF-κB reporter line identified 16 genes that are induced by TNFα or Lymphotoxin-β (LTβ) and implicated in the classic and/or alternative NF-κB pathways. Knockdown of TNFR, LTBR , or selected downstream signaling components established cross-talk between the classic and alternative NF-κB pathways. TNFα and LTβ induced differential gene expression involving the NF-κB, IFNγ, and STAT pathways, inflammatory cytokines, and metastasis-related genes. Improved survival was observed in HNSCC patients with elevated gene expression in T-cell activation, immune checkpoints, and IFNγ and STAT pathways. These gene signatures of NF-κB activation, which modulate inflammation and responses to the immune therapy, could serve as potential biomarkers in future clinical trials.

    更新日期:2019-11-01
  • The Atypical Receptor CCRL2 Is Essential for Lung Cancer Immune Surveillance
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    Annalisa Del Prete; Francesca Sozio; Tiziana Schioppa; Andrea Ponzetta; William Vermi; Stefano Calza; Mattia Bugatti; Valentina Salvi; Giovanni Bernardini; Federica Benvenuti; Annunciata Vecchi; Barbara Bottazzi; Alberto Mantovani; Silvano Sozzani

    CCRL2 is a nonsignaling seven-transmembrane domain receptor. CCRL2 binds chemerin, a protein that promotes chemotaxis of leukocytes, including macrophages and natural killer (NK) cells. In addition, CCRL2 controls the inflammatory response in different pathologic settings, such as hypersensitivity, inflammatory arthritis, and experimental autoimmune encephalitis. Here, we investigated the role of CCRL2 in the regulation of lung cancer–related inflammation. The genetic deletion of Ccrl2 promoted tumor progression in urethane-induced and in Kras G12D/+/ p53 LoxP lung tumor mouse models. Similarly, a Kras -mutant lung tumor displayed enhanced growth in Ccrl2 -deficient mice. This phenotype was associated with a reduced inflammatory infiltrate characterized by the impaired recruitment of several leukocyte populations including NK cells. Bone marrow chimeras showed that CCRL2 expression by the nonhematopoietic cell compartment was responsible for the increased tumor formation observed in Kras -mutant Ccrl2 -deficient mice. In human and mouse lungs, CCRL2 was expressed by a fraction of CD31+ endothelial cells, where it could control NK infiltration. Elevated CCRL2 expression in biopsies from human lung adenocarcinoma positively correlated with clinical outcome. These results provide evidence for a crucial role of CCRL2 in shaping an anti–lung tumor immune response.

    更新日期:2019-11-01
  • AXL Targeting Overcomes Human Lung Cancer Cell Resistance to NK- and CTL-Mediated Cytotoxicity
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    Stéphane Terry; Abderemane Abdou; Agnete S.T. Engelsen; Stéphanie Buart; Philippe Dessen; Stéphanie Corgnac; Davi Collares; Guillaume Meurice; Gro Gausdal; Véronique Baud; Pierre Saintigny; James B. Lorens; Jean-Paul Thiery; Fathia Mami-Chouaib; Salem Chouaib

    Immune resistance may arise from both genetic instability and tumor heterogeneity. Microenvironmental stresses such as hypoxia and various resistance mechanisms promote carcinoma cell plasticity. AXL, a member of the TAM (Tyro3, Axl, and Mer) receptor tyrosine kinase family, is widely expressed in human cancers and increasingly recognized for its role in cell plasticity and drug resistance. To investigate mechanisms of immune resistance, we studied multiple human lung cancer clones derived from a model of hypoxia-induced tumor plasticity that exhibited mesenchymal or epithelial features. We demonstrate that AXL expression is increased in mesenchymal lung cancer clones. Expression of AXL in the cells correlated with increased cancer cell–intrinsic resistance to both natural killer (NK)– and cytotoxic T lymphocyte (CTL)–mediated killing. A small-molecule targeting AXL sensitized mesenchymal lung cancer cells to cytotoxic lymphocyte–mediated killing. Mechanistically, we showed that attenuation of AXL-dependent immune resistance involved a molecular network comprising NF-κB activation, increased ICAM1 expression, and upregulation of ULBP1 expression coupled with MAPK inhibition. Higher ICAM1 and ULBP1 tumor expression correlated with improved patient survival in two non–small cell lung cancer (NSCLC) cohorts. These results reveal an AXL-mediated immune-escape regulatory pathway, suggest AXL as a candidate biomarker for tumor resistance to NK and CTL immunity, and support AXL targeting to optimize immune response in NSCLC.

    更新日期:2019-11-01
  • Blockade of CTLA-4 and PD-1 Enhances Adoptive T-cell Therapy Efficacy in an ICOS-Mediated Manner
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    Lewis Zhichang Shi; Sangeeta Goswami; Tihui Fu; Baoxiang Guan; Jianfeng Chen; Liangwen Xiong; Jan Zhang; Derek Ng Tang; Xuejun Zhang; Luis Vence; Jorge Blando; James P. Allison; Renata Collazo; Jianjun Gao; Padmanee Sharma

    Adoptive transfer of tumor-reactive T cells (ACT) has led to modest clinical benefit in the treatment of solid tumors. Failures with this therapy are primarily due to inadequate infiltration and poor function of adoptively transferred cells in the tumor microenvironment. To improve the efficacy of ACT, we combined ACT with dual blockade of CTLA-4 and PD-1. Treatment with anti–CTLA-4 plus anti–PD-1 compared with monotherapy resulted in durable antitumor responses, enhanced effector function of ACT, utilizing PMEL-1 transgenic (Tg+) CD8+ T cells, and improved survival. Using PMEL-1ICOS−/− mice, we showed that deletion of the inducible T-cell costimulator (ICOS) receptor abolished the therapeutic benefits, with selective downregulation of Eomesodermin (Eomes), interferon gamma (IFNγ), and perforin. Higher expression of IFNγ and Eomes was noted in human ICOShi CD8+ T cells compared with ICOSlow counterparts. Together, our data provide direct evidence that ACT combined with immune-checkpoint therapy confers durable antitumor responses, which largely depended on CD8+ T-cell–intrinsic expression of ICOS. Our study provides a foundation of testing combinatorial therapy of ACT of CD8 T cells and dual blocking of CTLA-4 and PD-1 in patients with melanoma.

    更新日期:2019-11-01
  • Eradication of Hepatocellular Carcinoma by NKG2D-Based CAR-T Cells
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    Bin Sun; Dong Yang; Hongjiu Dai; Xiuyun Liu; Ru Jia; Xiaoyue Cui; Wenxuan Li; Changchun Cai; Jianming Xu; Xudong Zhao

    Despite the great success of chimeric antigen receptor T (CAR-T)–cell therapy in the treatment of hematologic malignancies, CAR-T–cell therapy is limited in solid tumors, including hepatocellular carcinoma (HCC). NK group 2 member D (NKG2D) ligands (NKG2DL) are generally absent on the surface of normal cells but are overexpressed on malignant cells, offering good targets for CAR-T therapy. Indeed, analysis of The Cancer Genome Atlas and HCC tumor samples showed that the expression of most NKG2DLs was elevated in tumors compared with normal tissues. Thus, we designed a novel NKG2D-based CAR comprising the extracellular domain of human NKG2D, 4-1BB, and CD3ζ signaling domains (BBz). NKG2D-BBz CAR-T cells efficiently killed the HCC cell lines SMMC-7721 and MHCC97H in vitro , which express high levels of NKG2DLs, whereas they less efficiently killed NKG2DL-silenced SMMC-7721 cells or NKG2DL-negative Hep3B cells. Overexpression of MICA or ULBP2 in Hep3B improved the killing capacity of NKG2D-BBz CAR-T cells. T cells expressing the NKG2D-BBz CAR effectively eradicated SMMC-7721 HCC xenografts. Collectively, these results suggested that NKG2D-BBz CAR-T cells could potently eliminate NKG2DL-high HCC cells both in vitro and in vivo , thereby providing a promising therapeutic intervention for patients with NKG2DL-positive HCC.

    更新日期:2019-11-01
  • Single-Cell Transcriptome Analysis Reveals Gene Signatures Associated with T-cell Persistence Following Adoptive Cell Therapy
    Cancer Immunol. Res. (IF 8.619) Pub Date : 2019-11-01
    Yong-Chen Lu; Li Jia; Zhili Zheng; Eric Tran; Paul F. Robbins; Steven A. Rosenberg

    Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can mediate responses in some patients with metastatic epithelial cancer. Identifying gene signatures associated with successful ACT might enable the development of improved therapeutic approaches. The persistence of transferred T cells in the peripheral blood is one indication of clinical effectiveness, but many T-cell and host factors may influence T-cell persistence. To limit these variables, we previously studied a patient with metastatic colorectal cancer treated with polyclonal TILs targeting the KRAS (G12D) hotspot mutation, who experienced a partial response for 9 months. Three dominant clonotypes specifically recognizing KRAS(G12D) epitopes were identified, but we found that only two clonotypes persisted 40 days after ACT. Because of these findings, in this study, we performed the single-cell transcriptome analysis of the infused TILs. The analysis revealed a total of 472 genes that were differentially expressed between clonotypes 9.1-NP and 9.2-P single cells, and 528 genes between 9.1-NP and 10-P. Following these clonotypes in the peripheral blood after ACT, the gene expression patterns changed, but IL7R, ITGB1, KLF2 , and ZNF683 remained expressed in the persistent 9.2-P and 10-P cells, compared with the nonpersistent 9.1-NP cells. In addition, four autologous TILs, which were used for treatment but persisted poorly 1 month after ACT, did not express the gene profiles associated with persistence. These results suggest that certain TIL populations possess a unique gene expression profile that can lead to the persistence of T cells. Thus, this single-patient study provides insight into how to improve ACT for solid cancer.

    更新日期:2019-11-01
Contents have been reproduced by permission of the publishers.
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