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The exonuclease TREX1 constitutes an innate immune checkpoint limiting cGAS/STING-mediated antitumor immunity Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-03-15 Junghyun Lim, Ryan Rodriguez, Katherine Williams, John Silva, Alan G. Gutierrez, Paul Tyler, Faezzah Baharom, Tao Sun, Eva Lin, Scott Martin, Brandon D. Kayser, Robert J. Johnston, Ira Mellman, Lélia Delamarre, Nathaniel R. West, Sören Müller, Yan Qu, Klaus Heger
The DNA exonuclease TREX1 (Three-prime repair exonuclease 1) is critical for preventing autoimmunity in mice and humans by degrading endogenous cytosolic DNA, which otherwise triggers activation of the innate cGAS/STING pathway leading to the production of type I IFNs. Since tumor cells are prone to aberrant cytosolic DNA accumulation, we hypothesized that they are critically dependent on TREX1 activity
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Chronic stress exacerbates the immunosuppressive microenvironment and progression of gliomas by reducing secretion of CCL3 Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-03-04 Xu Wang, Long Zhang, Yi Zhou, Yan Wang, Xiang Wang, Yining Zhang, Ankang Quan, Yufei Mao, Yu Zhang, Ji Qi, Zhongyu Ren, Linbo Gu, Rutong Yu, Xiuping Zhou
As understanding of cancer has deepened, increasing attention has been turned to the roles of psychological factors, especially chronic stress–induced depression, in the occurrence and development of tumors. However, whether and how depression affects the progression of gliomas are still unclear. In this study, we have revealed that chronic stress inhibited the recruitment of tumor-associated macrophages
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Intratumoral TREX1 induction promotes immune evasion by limiting type I interferon Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-26 Eléonore Toufektchan, Alexandra Dananberg, Josefine Striepen, James H. Hickling, Abraham Shim, Yanyang Chen, Ashley Nichols, Mercedes A. Duran Paez, Lisa Mohr, Samuel F. Bakhoum, John Maciejowski
Chromosomal instability is a hallmark of human cancer that is associated with aggressive disease characteristics. Chromosome mis-segregations help fuel natural selection, but they risk provoking a cGAS-STING immune response through the accumulation of cytosolic DNA. The mechanisms of how tumors benefit from chromosomal instability while mitigating associated risks, such as enhanced immune surveillance
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High dimensional analyses reveal IL-15 enhances activation of Sipuleucel-T lymphocyte subsets and reverses immunoresistance Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-26 Muhammad A. Saeed, Bo Peng, Kevin Kim, Kavita Rawat, Lindsey M. Kuehm, Zoe R. Siegel, Ariel Borkowski, Nabih Habib, Brian Van Tine, Nadeem Sheikh, Vu Tuyen, Daniel L.J. Thorek, Todd A. Fehniger, Russell K. Pachynski
Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ~60%) of sip-T
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The TOPK inhibitor HI-TOPK-032 enhances CAR T-cell therapy of hepatocellular carcinoma by upregulating memory T cells Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-26 Qunfang Zhang, Fang Zheng, Yuchao Chen, Chun-Ling Liang, Huazhen Liu, Feifei Qiu, Yunshan Liu, Hongfeng Huang, Weihui Lu, Zhenhua Dai
Chimeric antigen receptor (CAR) T cells are emerging as an effective antitumoral therapy. However, their therapeutic effects on solid tumors are limited due to their short survival time and the immunosuppressive tumor microenvironment. Memory T cells respond more vigorously and persist longer than their naive/effector counterparts. Therefore, promoting CAR T-cell development into memory T cells could
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ILT2 and ILT4 drive myeloid suppression via both overlapping and distinct mechanisms Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-23 Jane Tian, Amir M. Ashique, Sabrina Weeks, Tian Lan, Hong Yang, Hung-I H. Chen, Christina Song, Kikuye Koyano, Kalyani Mondal, Daniel Tsai, Isla Cheung, Mehrdad Moshrefi, Avantika Kekatpure, Bin Fan, Betty Li, Samir Qurashi, Lauren Rocha, Jonathan Aguayo, Col Rodgers, Marchelle Meza, Darren Heeke, Sara M. Medfisch, Chun Chu, Shelley Starck, Nandini Pal. Basak, Satish Sankaran, Mohit Malhotra, Suzanne
Solid tumors are dense three-dimensional (3D) multi-cellular structures that enable efficient receptor–ligand trans interactions via close cell–cell contact. Immunoglobulin-like transcript (ILT)2 and ILT4 are related immune suppressive receptors that play a role in the inhibition of myeloid cells within the tumor microenvironment. The relative contributions of ILT2 and ILT4 to immune inhibition in
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ANXA3-rich exosomes derived from tumor-associated macrophages regulate ferroptosis and lymphatic metastasis of laryngeal squamous cell carcinoma Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-23 Licheng Xu, Wenjing Li, Danxi Liu, Jing Cao, Jingchun Ge, Xinyu Liu, Yue Wang, Yujian Teng, Pengyan Liu, Xinyue Guo, Chen He, Ming Liu, Linli Tian
Tumor-associated macrophages (TAMs) induce immunosuppression in laryngeal squamous cell carcinoma (LSCC). The interaction between LSCC cells and TAMs affects the progression of laryngeal cancer through exosomes, but the underlying molecular mechanism remains unclear. Proteomics analysis of TAMs isolated from human laryngeal tumor tissues obtained from patients with confirmed lymphatic metastasis revealed
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Machine learning links T-cell function and spatial localization to neoadjuvant immunotherapy and clinical outcome in pancreatic cancer Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-21 Katie E. Blise, Shamilene Sivagnanam, Courtney B. Betts, Konjit Betre, Nell Kirchberger, Benjamin J. Tate, Emma E. Furth, Andressa Dias Costa, Jonathan A. Nowak, Brian M. Wolpin, Robert H. Vonderheide, Jeremy Goecks, Lisa M. Coussens, Katelyn T. Byrne
Tumor molecular datasets are becoming increasingly complex, making it nearly impossible for humans alone to effectively analyze them. Here, we demonstrate the power of using machine learning (ML) to analyze a single-cell, spatial, and highly multiplexed proteomic dataset from human pancreatic cancer and reveal underlying biological mechanisms that may contribute to clinical outcome. We designed a multiplex
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Immunomodulatory Effects of RANK/RANKL Blockade in Patients with Cancer Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-19 Elham Nasrollahi, Diwakar Davar
In cancer, multiple factors converge upon receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) signaling to promote the development of bone metastases; agents that inhibit RANKL signaling reduce skeletal-related events (SRE) in patients with cancer. In addition, RANKL signaling is important in augmenting the ability of dendritic cells (DC) to stimulate both naïve T-cell proliferation
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Tsyn-seq: a T cell synapse–based antigen identification platform Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-16 Yimei Jin, Takahiko Miyama, Alexandria Brown, Tomo Hayase, Xingzhi Song, Anand K. Singh, Licai Huang, Ivonne I. Flores, Lauren K. McDaniel, Israel Glover, Taylor M. Halsey, Rishika Prasad, Valerie Chapa, Saira Ahmed, Jianhua Zhang, Kunal Rai, Christine B. Peterson, Gregory Lizee, Jennifer Karmouch, Eiko Hayase, Jeffrey J. Molldrem, Chia-Chi Chang, Wen-Bin Tsai, Robert R. Jenq
Tools for genome-wide rapid identification of peptide–major histocompatibility complex targets of T-cell receptors (TCRs) are not yet universally available. We present a new antigen screening method, the T-synapse (Tsyn) reporter system, which includes antigen-presenting cells (APCs) with a Fas-inducible NF-κB reporter and T cells with a nuclear factor of activated T cells (NFAT) reporter. To functionally
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Neutrophils mediate protection against colitis and carcinogenesis by controlling bacterial invasion and IL-22 production by γδ T cells Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-13 Silvia Carnevale, Andrea Ponzetta, Anna Rigatelli, Roberta Carriero, Simone Puccio, Domenico Supino, Giovanna Grieco, Piera Molisso, Irene Di Ceglie, Francesco Scavello, Chiara Perucchini, Fabio Pasqualini, Camilla Recordati, Claudio Tripodo, Beatrice Belmonte, Andrea Mariancini, Paolo Kunderfranco, Giuseppe Sciumè, Enrico Lugli, Eduardo Bonavita, Elena Magrini, Cecilia Garlanda, Alberto Mantovani
Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. This study aims to dissect the role of neutrophils in these pathological contexts by using a rigorous genetic approach. Neutrophil-deficient
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High-specificity CRISPR-mediated genome engineering in anti-BCMA allogeneic CAR T cells suppresses allograft rejection in preclinical models Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-12 Émilie Degagné, Paul D. Donohoue, Suparna Roy, Jessica Scherer, Tristan W. Fowler, Ryan T. Davis, Gustavo A. Reyes, George Kwong, Morena Stanaway, Vanina Larroca Vicena, Devin Mutha, Raymond Guo, Leslie Edwards, Benjamin Schilling, McKay Shaw, Stephen C. Smith, Bryan Kohrs, Heinrich J. Kufeldt, Glen Churchward, Finey Ruan, David B. Nyer, Kyle McSweeney, Matthew J. Irby, Christopher K. Fuller, Lynda
Allogeneic chimeric antigen receptor (CAR) T-cell therapies hold the potential to overcome many of the challenges associated with patient-derived (autologous) CAR T cells. Key considerations in the development of allogeneic CAR T-cell therapies include prevention of GvHD and suppression of allograft rejection. Here we describe preclinical data supporting the ongoing first-in-human clinical study, the
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Intragenic Rearrangement Burden Associates with Immune Cell Infiltration and Response to Immune Checkpoint Blockade in Cancer Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-12 Han Zhang, Sanghoon Lee, Renee R. Muthakana, Binfeng Lu, David N. Boone, Daniel Lee, Xiao-Song Wang
Immune checkpoint blockade (ICB) can induce durable cancer remission. However, only a small subset of patients gains benefits. While tumor mutation burden (TMB) differentiates responders from nonresponders in some cases, it is a weak predictor in tumor types with low mutation rates. Thus, there is an unmet need to discover a new class of genetic aberrations that predict ICB responses in these tumor
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Gut mycobiota dysbiosis is associated with melanoma and response to anti-PD-1 therapy Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-05 Natalia Szóstak, Luiza Handschuh, Anna Samelak-Czajka, Katarzyna Tomela, Bernadeta Pietrzak, Marcin Schmidt, Łukasz Galus, Jacek Mackiewicz, Andrzej Mackiewicz, Piotr Kozlowski, Anna Philips
Recent research indicates that gut microbiota may be vital in the advancement of melanoma. In this study we found that melanoma patients exhibited a distinct gut mycobiota structure compared to healthy participants. Candida albicans, Candida dubliniensis, and Neurospora crassa were more abundant in samples from patients with melanoma, while Saccharomyces cerevisiae and Debaryomyces hansenii were less
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NCI Resources for Cancer Immunoprevention Research Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-02-01 Shizuko Sei, Sudhir Srivastava, Halonna R. Kelly, Mark Steven. Miller, Wolfgang W. Leitner, Robert H. Shoemaker, Eva Szabo, Philip E. Castle
Cancer prevention and early detection, the first two of the eight primary goals of the National Cancer Plan released in April 2023, are at the forefront of the nation’s strategic efforts to reduce cancer incidence and mortality. The Division of Cancer Prevention (DCP) of the National Cancer Institute (NCI) is the federal government’s principal component devoted to promoting and supporting innovative
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An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-30 Yaochuan Zhang, Yifu Song, Xiaoliang Wang, Mengwu Shi, Yibin Lin, Dongxia Tao, Sheng Han
Extensive infiltration by tumor-associated macrophages (TAM) in combination with myeloid-derived suppressor cells constitute the immunosuppressive microenvironment and promote the malignant phenotype of gliomas. The aggressive mesenchymal (MES)-subtype glioma stem cells (GSC) are prominent in the immunosuppressive microenvironment of gliomas. However, the underlying immune-suppressive mechanisms are
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The immune suppressor IGSF1 as a potential target for cancer immunotherapy Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-30 Dong-In Koh, Minki Lee, Yoon Sun Park, Jae-Sik Shin, Joseph Kim, Yea Seong Ryu, Jun Hyung Lee, Seunggeon Bae, Mi So Lee, Jun Ki Hong, Hong Rae Jeong, Mingee Choi, Seung-Woo Hong, Dong Kwan Kim, Hyun-kyung Lee, Bomi Kim, Yoo Sang Yoon, Dong-Hoon Jin
The development of first-generation immune checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 ushered in a new era in anticancer therapy. While immune checkpoint blockade therapies have shown clinical success, a significant number of patients yet fail to benefit. According to recent reports, many studies are underway to discover next-generation immunotherapeutic targets. Here, we identified a novel
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Dual chimeric antigen receptor T cells targeting CD38 and SLAMF7 with independent signalling demonstrate preclinical efficacy and safety in Multiple Myeloma Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-30 Nathalie Roders, Cecilia Nakid-Cordero, Fabio Raineri, Maxime Fayon, Audrey Abecassis, Caroline Choisy, Elisabeth Nelson, Claire Maillard, David Garrick, Alexis Talbot, Jean-Paul Fermand, Bertrand Arnulf, Jean-Christophe Bories
Chimeric antigen receptor T-cell (CAR-T) therapy for multiple myeloma (MM) targeting B-cell maturation antigen (BCMA) induces high overall response rates. However, relapse still occurs and novel strategies for targeting MM cells using CAR-T are needed. SLAMF7 (also known as CS1) and CD38 on tumour plasma cells represent potential alternative targets for CAR-T in MM, but their expression on activated
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Immune modulation with RANKL blockade through denosumab treatment in patients with cancer Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-29 Hewitt Chang, Jaqueline Marquez Garcia, Brandon K. Chen, Daniel M. Kim, Michael L. Cheng, Eric V. Liu, Hai Yang, Li Zhang, Meenal Sinha, Alexander Cheung, Serena S. Kwek, Eric D. Chow, Mark Bridge, Rahul R. Aggarwal, Terence W. Friedlander, Eric J. Small, Mark Anderson, Lawrence Fong
Denosumab is a fully human monoclonal antibody that binds receptor activator of nuclear factor-κB ligand (RANKL). It is routinely administered to cancer patients to reduce the incidence of new bone metastasis. RANK–RANKL interactions regulate bone turnover by controlling osteoclast recruitment, development, and activity. However, these interactions also can regulate immune cells including dendritic
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Lymph Node–Targeted Vaccine Boosting of TCR T-cell Therapy Enhances Antitumor Function and Eradicates Solid Tumors Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-25 Dylan J. Drakes, Abdulraouf M. Abbas, Jacqueline Shields, Martin P. Steinbuck, Aniela Jakubowski, Lochana M. Seenappa, Christopher M. Haqq, Peter C. DeMuth
T-cell receptor (TCR)–modified T-cell therapies have shown promise against solid tumors, but overall therapeutic benefits have been modest due in part to suboptimal T-cell persistence and activation in vivo, alongside potential tumor antigen escape. In this study, we demonstrate an approach to enhance the in vivo persistence and function of TCR T cells through combination with Amphiphile (AMP) vaccination
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Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-23 Jiang Chen, Zohreh Amoozgar, Xin Liu, Shuichi Aoki, Zelong Liu, Sarah M. Shin, Aya Matsui, Alexei Hernandez, Zhangya Pu, Stefan Halvorsen, Pin-Ji Lei, Meenal Datta, Lingling Zhu, Zhiping Ruan, Lei Shi, Daniel Staiculescu, Koetsu Inoue, Lance L. Munn, Dai Fukumura, Peigen Huang, Slim Sassi, Nabeel Bardeesy, Won Jin Ho, Rakesh K. Jain, Dan G. Duda
Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the PD1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-CTLA-4 when combined with anti-PD1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy
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T cell states, repertoire and function in classical Hodgkin lymphoma revealed through single-cell analyses Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-19 Xiufen Chen, Jovian Yu, Girish Venkataraman, Sonali M. Smith, Mengjie Chen, Alan Cooper, Sravya Tumuluru, Joshua D. Brody, James Godfrey, Justin Kline
The classical Hodgkin lymphoma (cHL) environment is comprised of a dense and complex immune cell infiltrate interspersed with rare malignant Hodgkin-Reed-Sternberg (HRS) cells. HRS cells are actively surveilled by endogenous T cells, but data linking phenotypic and functional T cell states with clonality at the single cell level in cHL is lacking. To address this knowledge gap, we performed paired
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Translating Science into Survival: Report on the Seventh International Cancer Immunotherapy Conference Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-17 Jan D. Beck, Juliana Kenski, Milena Perrone, Arianna Pocaterra, Karen Honey
From September 20 to 23, 2023, the Seventh International Cancer Immunotherapy Conference was hosted jointly by the Cancer Research Institute, the European Network for Cancer Immunotherapy (ENCI), and the American Association for Cancer Research (AACR) in Milan, Italy. The four-day event covered the latest advances in cancer immunology and immunotherapy.
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Tumor-Derived RAB21+ABHD12+ sEVs Drive the Premetastatic Microenvironment in the Lung Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-12 Kun Wu, Yan Li, Yikang Ji, Chun Liu, Xiaoning Wang, Haiyan Guo, Jianjun Zhang, Yue He
Tumor metastasis is a spatial and temporal process that starts with remodeling to generate a proper premetastatic niche in a distant tissue. Infiltration of immunosuppressive macrophages is one of the notable characteristics in the premetastatic niche, which is a fundamental requirement for primary tumor metastasis. Here, we demonstrated that small extracellular vesicles (sEV) carrying RAB21 homed
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Neutralizing antibodies impair the oncolytic efficacy of reovirus but permit effective combination with T cell–based immunotherapies Cancer Immunol. Res. (IF 10.1) Pub Date : 2024-01-09 Christianne Groeneveldt, Priscilla Kinderman, Lisa Griffioen, Olivia Rensing, Camilla Labrie, Diana J M. van den Wollenberg, Rob C. Hoeben, Matthew Coffey, Houra Loghmani, Els M.E. Verdegaal, Marij J.P. Welters, Sjoerd H. van der Burg, Thorbald van Hall, Nadine van Montfoort
Reovirus type 3 Dearing (Reo), manufactured for clinical application as Pelareorep, is an attractive anticancer agent under evaluation in multiple phase 2 clinical trials for the treatment of solid tumors. It elicits its anticancer efficacy by inducing both oncolysis and intratumoral T-cell influx. Since most people have been preexposed to Reo, neutralizing antibodies (NAbs) are prevalent in cancer
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FcγRIIB is an immune checkpoint limiting the activity of Treg-targeting antibodies in the tumor microenvironment Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-26 David A. Knorr, Lucas Blanchard, Rom S. Leidner, Shawn M. Jensen, Ryan Meng, Andrew Jones, Carmen Ballesteros-Merino, Richard B. Bell, Maria Baez, Alessandra Marino, David Sprott, Carlo B. Bifulco, Brian Piening, Rony Dahan, Juan C. Osorio, Bernard A. Fox, Jeffrey V. Ravetch
Preclinical murine data indicate that Fc-dependent depletion of intratumoral regulatory T cells (Tregs) is a major mechanism of action of anti–CTLA-4. However, the two main antibodies administered to patients (Ipilimumab and Tremelimumab) do not recapitulate these effects. Here, we investigate the underlying mechanisms responsible for the limited Treg depletion observed with these therapies. Using
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LILRB3 supports immunosuppressive activity of myeloid cells and tumor development Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-19 Ryan Huang, Xiaoye Liu, Jaehyup Kim, Hui Deng, Mi Deng, Xun Gui, Heyu Chen, Guojin Wu, Wei Xiong, Jingjing Xie, Cheryl Lewis, Jade Homsi, Xing Yang, Chengcheng Zhang, Yubo He, Qi Lou, Caroline Smith, Samuel John, Ningyan Zhang, Zhiqiang An, Chengcheng Zhang
The existing T cell–centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily
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Immune-related colitis is associated with fecal microbial dysbiosis and can be mitigated by fecal microbiota transplantation Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-18 Arielle Elkrief, Nicholas R. Waters, Natalie Smith, Anqi Dai, John Slingerland, Nathan Aleynick, Binita Febles, Pooja Gogia, Nicholas D. Socci, Melissa Lumish, Paul A. Giardina, Jamie E. Chaft, Juliana Eng, Robert J. Motzer, Robin B. Mendelsohn, Kate A. Markey, Mingqiang Zhuang, Yanyun Li, Zhifan Yang, Travis J. Hollmann, Charles M. Rudin, Marcel R.M. van den Brink, Jinru Shia, Susan DeWolf, Adam J
Colitis induced by treatment with immune checkpoint inhibitors (ICI), termed irColitis, is a substantial cause of morbidity complicating cancer treatment. We hypothesized that abnormal fecal microbiome features would be present at the time of irColitis onset, and that restoring the microbiome with fecal transplant from a healthy donor would mitigate disease severity. Herein, we present fecal microbiota
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M9657 is a bispecific tumor-targeted anti-CD137 agonist that induces MSLN-dependent antitumor immunity without liver inflammation Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-13 Chunxiao Xu, Xueyuan Zhou, Lindsay Webb, Sireesha Yalavarthi, Wenxin Zheng, Somdutta Saha, Rene Schweickhardt, Maria Soloviev, Molly H. Jenkins, Susanne Brandstetter, Natalya Belousova, Marat Alimzhanov, Brian Rabinovich, Amit M. Deshpande, Neil Brewis, Laura Helming
The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated
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Single-cell transcriptomics reveals the heterogeneity of the immune landscape of IDH-wildtype high-grade gliomas Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-13 Xiaojuan Ran, Jian Zheng, Lingchao Chen, Zhen Xia, Yin Wang, Chengfang Sun, Chen Guo, Peng Lin, Fuyi Liu, Chun Wang, Jianguo Zhou, Chongran Sun, Qichang Liu, Jianzhu Ma, Zhiyong Qin, Xiangdong Zhu, Qi Xie
Isocitrate dehydrogenase (IDH)-wildtype (WT) high-grade gliomas, especially glioblastomas, are highly aggressive and have an immunosuppressive tumor microenvironment. Although tumor-infiltrating immune cells are known to play a critical role in glioma genesis, their heterogeneity and intercellular interactions remain poorly understood. In this study, we constructed a single-cell transcriptome landscape
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Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-11 Ayesha B. Alvero, Alexandra Fox, Bhaskara Reddy Madina, Marie M. Krady, Radhika Gogoi, Hussein Chehade, Valerian Nakaar, Bijan Almassian, Timur O. Yarovinsky, Thomas Rutherford, Gil Mor
Current immunotherapies have proven effective in strengthening anti-tumor immune responses, but constant opposing signals from tumor cells and the surrounding microenvironment eventually lead to immune escape. We hypothesized that in situ release of antigens and regulation of both the innate and adaptive arms of the immune system would provide a robust and long-term anti-tumor effect by creating immunological
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Intracellular K+ Limits T-cell Exhaustion and Preserves Antitumor Function Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-08 Camille Collier, Kelly Wucherer, Matthew McWhorter, Chelsea Jenkins, Alexandra Bartlett, Rahul Roychoudhuri, Robert Eil
T cells are often compromised within cancers, allowing disease progression. We previously found that intratumoral elevations in extracellular K+, related to ongoing cell death, constrained CD8+ T-cell Akt–mTOR signaling and effector function. To alleviate K+-mediated T-cell dysfunction, we pursued genetic means to lower intracellular K+. CD8+ T cells robustly and dynamically express the Na+/K+ ATPase
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CD8+ T Cells Keep Their (K+)urrency for Function Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-08 Alma Banuelos, Henrique Borges da Silva
CD8+ T-cell responses are influenced by ion abundance, which can widely vary within the tumor microenvironment. In this issue, Collier and colleagues investigated how intracellular versus extracellular potassium ion (K+) regulates intratumoral CD8+ T cells. They show that, while excessive extracellular K+ induces exhaustion, intracellular K+ is needed for protection from dysfunction. This work shows
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Innate Lymphoid Cells in Bladder Cancer: From Mechanisms of Action to Immune Therapies Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-07 Onika D.V. Noel, Zaineb Hassouneh, Robert S. Svatek, Neelam Mukherjee
Bladder tumors have a high mutational burden and tend to be responsive to immune therapies; however, response rates remain modest. To date, immunotherapy in bladder cancer has largely focused on enhancing T-cell immune responses in the bladder tumor microenvironment. It is anticipated that other immune cells, including innate lymphoid cells (ILC), which play an important role in bladder oncogenesis
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RALDH1 inhibition shows immunotherapeutic efficacy in hepatocellular carcinoma Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-05 Pengfei Yu, Shuwen Cao, Shyh-Ming Yang, Ganesha Rai, Natalia J. Martinez, Adam Yasgar, Alexey V. Zakharov, Anton Simeonov, William A. Molina-Arocho, Graham P. Lobel, Hesham Mohei, Alexis L. Scott, Li Zhai, Emma E. Furth, M Celeste. Simon, Malay Haldar
Globally, hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related death. We previously identified an immune evasion pathway whereby tumor cells produce retinoic acid (RA) to promote differentiation of intratumoral monocytes into pro-tumor macrophages. Retinaldehyde dehydrogenase 1 (RALDH1), RALDH2, and RALDH3 are the three isozymes that catalyze
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Engagement of CD99 activates distinct programs in Ewing sarcoma and macrophages Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-12-05 Maria Cristina Manara, Cristina Manferdini, Camilla Cristalli, Marianna Carrabotta, Spartaco Santi, Alessandra De Feo, Giulia Caldoni, Michela Pasello, Lorena Landuzzi, Pier-Luigi Lollini, Francesca Salamanna, Sabrina Dominici, Valentina Fiori, Mauro Magnani, Gina Lisignoli, Katia Scotlandi
Ewing sarcoma (EWS) is the second most common pediatric bone tumor. The EWS tumor microenvironment is largely recognized as immune-cold, with macrophages being the most abundant immune cells and their presence associated with worse patient prognosis. Expression of CD99 is a hallmark of EWS cells, and its targeting induces inhibition of EWS tumor growth through a poorly understood mechanism. In this
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A metabolic axis of immune intractability Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-11-21 Dominique C. Hinshaw, Meet Patel, Lalita A. Shevde
Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are re-enacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits
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Separating the Good from the Bad: Tumor-Infiltrating Tregs Have Increased Fucosylation Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-11-15 Stephanie Silveria, Michel DuPage
Regulatory T cells (Treg) can suppress antitumor immune responses, and their presence in tumors is associated with worse prognoses in most cancers. Strategies to neutralize Treg-mediated suppression in tumors without immune-related adverse events, however, are challenging due to the essential role of Tregs in maintaining immune homeostasis. In this issue, Pinioti and colleagues identify fucosylation
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Combination anti-PD-1 and electroacupuncture induces a potent anti-tumor immune response in microsatellite-stable colorectal cancer Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-11-13 Yuan Wang, Fengyi Liu, Xiaoxue Du, Jiaqi Shi, Rui Yu, Shuang Li, Ruisi Na, Ying Zhao, Meng Zhou, Ying Guo, Liang Cheng, Guangyu Wang, Tongsen Zheng
Programmed death receptor-1 (PD-1) inhibitors are ineffective against microsatellite-stable (MSS) colorectal cancer (CRC). Electroacupuncture (EA) has onco-suppressive and immunomodulatory properties. Here, we investigated the anti-tumor effects of EA and explored the feasibility of EA combined with anti-PD-1 in MSS CRC. Results showed that EA exerted its anti-tumor effect in an intensity-specific
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The tautomerase activity of tumor exosomal MIF promotes pancreatic cancer progression by modulating MDSC differentiation Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-11-13 Xuebing Jia, Jianbei Xi, Binle Tian, Yuanyuan Zhang, Zhilong Wang, Fan Wang, Zheng Li, Jiang Long, JianFei Wang, Guo-Huang Fan, Qi Li
Pancreatic cancer is a deadly disease that is largely resistant to immunotherapy, in part because of the accumulation of immunosuppressive cells in the tumor microenvironment (TME). Much evidence suggests that tumor-derived exosomes contribute to the immunosuppressive activity mediated by myeloid-derived suppressor cells (MDSCs) within the pancreatic cancer TME. However, the underlying mechanisms remain
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Battle Within the Sexes: Differences in Male and Female Immunity and the Impact on Antitumor Responses Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-11-08 Katey S. Hunt, Elise Alspach
The immune system plays critical roles in regulating tumor progression. However, despite established differences in male and female immune cell function, our appreciation of sex as a variable in antitumor immune responses is only beginning to develop. Recent findings in mice have demonstrated for the first time that disparities in cancer incidence between the sexes are driven in part by differences
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A Metabolic Gene Survey Pinpoints Fucosylation as a Key Pathway Underlying the Suppressive Function of Regulatory T Cells in Cancer Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-11-07 Sotiria Pinioti, Himal Sharma, Nina C. Flerin, Qian Yu, Amalia Tzoumpa, Sarah Trusso Cafarello, Elien De Bousser, Nico Callewaert, Guillaume Oldenhove, Susan Schlenner, Bernard Thienpont, Abhishek D. Garg, Mario Di Matteo, Massimiliano Mazzone
Forkhead box P3 (Foxp3)–expressing regulatory T cells (Treg) are the guardians of controlled immune reactions and prevent the development of autoimmune diseases. However, in the tumor context, their increased number suppresses antitumor immune responses, indicating the importance of understanding the mechanisms behind their function and stability. Metabolic reprogramming can affect Foxp3 regulation
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Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-11-06 Wei Yan, Rosa E. Menjivar, Monica E. Bonilla, Nina G. Steele, Samantha B. Kemp, Wenting Du, Katelyn L. Donahue, Kristee Brown, Eileen S. Carpenter, Faith R. Avritt, Valerie M. Irizarry-Negron, Sion Yang, William R. Burns, Yaqing Zhang, Marina Pasca di Magliano, Filip Bednar
Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAMs) are instrumental
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Bexmarilimab activates human tumor-associated macrophages to support adaptive immune responses in interferon-poor immune microenvironments Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-11-03 Jenna H. Rannikko, Petri Bono, Johanna Hynninen, Maija Hollmén
Immune checkpoint inhibitors show substantially greater efficacy in inflamed tumors characterized by pre-existing T cell infiltration and interferon (IFN) signaling than in non-inflamed, “cold”, tumors, which often remain immunotherapy resistant. The cancer immunotherapy bexmarilimab, which inhibits the scavenger receptor Clever-1 to release macrophage immunosuppression and activate adaptive immunity
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Tyrosine kinase inhibition activates intratumoral ϒδ T cells in gastrointestinal stromal tumor Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-11-03 Mark S. Etherington, Andrew N. Hanna, Benjamin D. Medina, Mengyuan Liu, Andrew D. Tieniber, Hyunjee V. Kwak, Katherine J. Tardy, Lillian Levin, Kevin J. Do, Ferdinand Rossi, Shan Zeng, Ronald P. DeMatteo
γδ T cells are a rare but potent subset of T cells with pleiotropic functions. They commonly reside within tumors but the response of γδ T cells to tyrosine kinase inhibition is unknown. To address this, we studied a genetically engineered mouse model of gastrointestinal stromal tumor (GIST) driven by oncogenic Kit signaling that responds to the Kit inhibitor imatinib. At baseline, γδ T cells were
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Lessons for the Next Generation of Scientists from the Second Annual Arthur and Sandra Irving Cancer Immunology Symposium Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-31 Christopher Alvarez-Breckenridge, Kristin G. Anderson, Ana Luisa Correia, Shadmehr Demehri, Huy Q. Dinh, Karen Olivia Dixon, Gavin P. Dunn, Laura Evgin, Jeremy Goc, Zinaida Good, Nir Hacohen, Patrick Han, Pavel Hanč, John Hickey, Kelly Kersten, Beiyun C. Liu, Aitziber Buque, Yuxuan ‘Phoenix’ Miao, J. Justin Milner, Yuri Pritykin, Ferdinando Pucci, Nicole E. Scharping, Lisa Sudmeier, Yufei Wang, Andreas
The Arthur and Sandra Irving Cancer Immunology Symposium has been created as a platform for established cancer immunologists to mentor trainees and young investigators as they launch their research career in the field. By sharing their different paths to success, the senior faculty mentors provide an invaluable resource to support the development of the next generation of leaders in the cancer immunology
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The Yin Yang of Complement and Cancer Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-30 Seppo Meri, Elena Magrini, Alberto Mantovani, Cecilia Garlanda
Cancer-related inflammation is a crucial component of the tumor microenvironment (TME). Complement activation occurs in cancer and supports the development of an inflammatory microenvironment. Complement has traditionally been considered a mechanism of immune resistance against cancer, and its activation is known to contribute to the cytolytic effects of antibody-based immunotherapeutic treatments
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Determinants for Antitumor and Protumor Effects of Programmed Cell Death Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-30 Samuel T. Workenhe, Jordon M. Inkol, Michael J. Westerveld, Shayla G. Verburg, Sarah M. Worfolk, Scott R. Walsh, Kaslyn L.F. Kallio
Cytotoxic anticancer therapies activate programmed cell death in the context of underlying stress and inflammatory signaling to elicit the emission of danger signals, cytokines, and chemokines. In a concerted manner, these immunomodulatory secretomes stimulate antigen presentation and T cell–mediated anticancer immune responses. In some instances, cell death–associated secretomes attract immunosuppressive
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T cell–Dependent Bispecific Therapy Enhances Innate Immune Activation and Antibody-Mediated Killing Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-30 Rickvinder Besla, Elicia Penuel, Geoffrey del Rosario, Ely Cosino, Szymon Myrta, Michael Dillon, Greg A. Lazar, Dorothee Nickles, Christoph Spiess, Shang-Fan Yu, Andrew G. Polson
T cell–retargeting therapies have transformed the therapeutic landscape for hematological diseases. T cell–dependent bispecific antibodies (TDBs) function as conditional agonists that induce a polyclonal T-cell response, resulting in target cell destruction and cytokine release. The relationship between this response and its effects on surrounding innate immune populations has not been fully explored
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Infusion Product TNFα, Th2, and STAT3 Activities are Associated with Clinical Responses to Transgenic T-cell Receptor Cell Therapy Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-23 Theodore S. Nowicki, Cole W. Peters, Crystal Quiros, Conner K. Kidd, Moe Kawakami, Alexandra M. Klomhaus, Ignacio Baselga-Carretero, Paula Kaplan-Lefko, Mignonette H. Macabali, Ivan Perez Garcilazo, Beata Berent-Maoz, Begoña Comin-Anduix, Antoni Ribas
Transgenic T-cell receptor (TCR) T cell–based adoptive cell therapies for solid tumors are associated with dramatic initial response rates, but there remain many instances of treatment failure and disease relapse. The association of infusion product cytokine profiles with clinical response has not been explored in the context of TCR T-cell therapy products. Single-cell antigen-dependent secretomic
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Spatial Distribution Of Immune Cells Drives Resistance To Neoadjuvant Chemotherapy In Triple-Negative Breast Cancer Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-19 Benedetta Donati, Francesca Reggiani, Federica Torricelli, Giacomo Santandrea, Teresa Rossi, Alessandra Bisagni, Elisa Gasparini, Antonino Neri, Laura Cortesi, Guglielmo Ferrari, Giancarlo Bisagni, Moira Ragazzi, Alessia Ciarrocchi
Neoadjuvant chemotherapy (NAC) alone or combined with target therapies represents the standard of care for localized triple-negative breast cancer (TNBC). However, only a fraction of patients have a response, necessitating better understanding of the complex elements in the TNBC ecosystem that establish continuous and multidimensional interactions. Resolving such complexity requires new spatially-defined
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Effective Antitumor Immunity Can be Triggered by Targeting VISTA in Combination with a TLR3-specific Adjuvant Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-17 Bo Wang, Ziwei Ou, Wenlong Zhong, Lin Huang, Wenjian Liao, Yiyu Sheng, Zhixing Guo, Junyu Chen, Wenjuan Yang, Ke Chen, Xiaodong Huang, Tenghao Yang, Tianxin Lin, Jian Huang
T cell control could not be unleashed in tumors resistant to anti-PD-1/PD-L1 treatment, which appears to be associated with inhibitory macrophages. V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a non-redundant immune checkpoint that can induce both T cell and myeloid cell immunosuppression. We determined high levels of VISTA+ immune cells were associated with advanced stage, and
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Tumor-reactive CD8+ T cells enter a TCF1+PD1– dysfunctional state Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-16 Jessica J. Roetman, Megan M. Erwin, Michael W. Rudloff, Natalie R. Favret, Carlos R. Detres Roman, Minna K.I. Apostolova, Kristen A. Murray, Ting-Fang Lee, Youngmin A. Lee, Mary Philip
T cells recognize several types of antigens in tumors, including aberrantly expressed, non-mutated proteins, which are therefore shared with normal tissue and referred to as self/shared-antigens (SSA), and mutated proteins or oncogenic viral proteins, which are referred to as tumor-specific antigens (TSA). Immunotherapies such as immune checkpoint blockade (ICB) can activate T-cell responses against
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Antitumor Immune Responses in B2M-Deficient Cancers Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-06 Davis Y. Torrejon, Mildred Galvez, Gabriel Abril-Rodriguez, Katie M. Campbell, Egmidio Medina, Agustin Vega-Crespo, Anusha Kalbasi, Begoña Comin-Anduix, Antoni Ribas
β2-microglobulin (B2M) is a critical component of the MHC class I molecule and is required to present tumor antigens to T cells. Its loss results in acquired resistance to immune checkpoint blockade (ICB) therapies. However, there have been well-documented cases of B2M-inactivated tumors responding to ICB, justifying investigation of how an antitumor immune response can be generated to tumors without
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Cancer Immunology and Immunotherapy Showcased in the AACR Cancer Progress Report 2023. Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-04 Padmanee Sharma,James P Allison
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Mitochondria Dictate Function and Fate of HSCs and T Cells Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-10-04 Yingxi Xu, Yi-Hsuan Chiang, Ping-Chih Ho, Nicola Vannini
Hematopoietic stem cells (HSC) and T cells are intimately related, lineage-dependent cell populations that are extensively used as therapeutic products for the treatment of hematologic malignancies and certain types of solid tumors. These cellular therapies can be life-saving treatments; however, their efficacies are often limited by factors influencing their activity and cellular properties. Among
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Considerations and Approaches for Cancer Immunotherapy in the Aging Host Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-09-28 Carlos O. Ontiveros, Clare E. Murray, Grace Crossland, Tyler J. Curiel
Advances in cancer immunotherapy are improving treatment successes in many distinct cancer types. Nonetheless, most tumors fail to respond. Age is the biggest risk for most cancers, and the median population age is rising worldwide. Advancing age is associated with manifold alterations in immune cell types, abundance, and functions, rather than simple declines in these metrics, the consequences of
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Antigen priming induces functional reprogramming in iNKT cells via metabolic and epigenetic regulation: An insight into iNKT cell-based anti-tumor immunotherapy Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-09-27 Huimin Zhang, Sanwei Chen, Yuwei Zhang, Chenxi Tian, Jun Pan, Yu Wang, Shiyu Bai, Qielan Wu, Miya Su, Di Xie, Sicheng Fu, Shuhang Li, Jing Zhang, Yusheng Chen, Shasha Zhu, Yeben Qian, Li Bai
Dysfunction of intratumoral invariant natural killer T (iNKT) cells hinders their anti-tumor efficacy, but the underlying mechanisms and the relationship with endogenous antigen priming remain to be explored. Here, we report that antigen priming leads to metabolic reprogramming and epigenetic remodeling, which causes functional reprogramming in iNKT cells, characterized by limited cytokine responses
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Long-read sequencing reveals alternative splicing-driven, shared immunogenic neoepitopes regardless SF3B1 status in uveal melanoma Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-09-27 Tengteng Yao, Zhe Zhang, Qian Li, Rui Huang, Yanhong Hong, Chen Li, Feng Zhang, Yingying Huang, Yan Fang, Qin Cao, Xiaoliang Jin, Chunliang Li, Zefeng Wang, Xinhua (James) Lin, Lingjie Li, Wu Wei, Zhaoyang Wang, Jianfeng Shen
Tumor-specific neoepitopes are promising targets in cancer immunotherapy. However, identification of functional tumor-specific neoepitopes remains challenging. In addition to the most common source, single-nucleotide variants (SNVs), alternative splicing (AS) represents another rich source of neoepitopes and can be utilized in cancers with low SNVs such as uveal melanoma (UM). UM, the most prevalent
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AACR Cancer Centers Alliance: Fostering Collaboration and Innovation to Advance Lifesaving Scientific Discoveries for Patients Cancer Immunol. Res. (IF 10.1) Pub Date : 2023-09-21 Carlos L. Arteaga, John L. Cleveland, Margaret Foti, Ruben A. Mesa, Louis M. Weiner, Cheryl L. Willman, David A. Tuveson
Basic and clinical cancer research discoveries stemming from the nation's cancer centers have markedly improved outcomes for many cancer patients. Despite this forward momentum in our progress against this complex disease, cancer in all its forms remains a major public health challenge that touches the lives of nearly every American, either directly or indirectly. The newly formed AACR Cancer Centers