{"title":"Mathematical modeling predicts optimal immune checkpoint inhibitor and radiotherapy combinations and timing of administration.","authors":"Shunsuke A Sakai, Koichi Saeki, SungGi Chi, Yamato Hamaya, Junyan Du, Masaki Nakamura, Hidehiro Hojo, Takashi Kojima, Yoshiaki Nakamura, Hideaki Bando, Motohiro Kojima, Ayako Suzuki, Yutaka Suzuki, Tetsuo Akimoto, Katsuya Tsuchihara, Hiroshi Haeno, Riu Yamashita, Shun-Ichiro Kageyama","doi":"10.1158/2326-6066.CIR-24-0610","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0610","url":null,"abstract":"<p><p>Radiotherapy (RT) combined with immune checkpoint inhibitor (ICI) therapy has attracted substantial attention due to its potential to improve outcomes for patients with several types of cancer. However, the optimal administration timepoints and drug combinations remain unclear because the mechanisms underlying RT-induced changes in immune checkpoint molecule expression and interaction with their ligand(s) remain unclear. Herein, we demonstrated the dynamics of lymphocyte-mediated molecular interactions in tissue samples from esophageal cancer patients throughout RT schedules. Single-cell RNA-sequencing and spatial transcriptomic analyses were performed to investigate the dynamics of these interactions. The biological signal in lymphocytes transitioned from innate to adaptive immune reaction, with increases in ligand-receptor interactions, such as PD-1-PD-L1, CTLA4-CD80/86, and TIGIT-PVR interactions. A mathematical model was constructed to predict the efficacy of five types of ICI when administered at four different timepoints. The model suggested that concurrent anti-PD-1/PD-L1 therapy or concurrent/adjuvant anti-CTLA-4/TIGIT therapy would exert a maximal effect with RT. This study provides rationale for clinical trials of RT combined with defined ICI therapy, and these findings will support future studies to search for more effective targets and timing of therapy administration.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yaiza Senent, Ana Remírez, David Repáraz, Diana Llopiz, Daiana P Celias, Cristina Sainz, Rodrigo Entrialgo-Cadierno, Lucia Suarez, Ana Rouzaut, Diego Alignani, Beatriz Tavira, John D Lambris, Trent M Woodruff, Carlos E de Andrea, Brian Ruffell, Pablo Sarobe, Daniel Ajona, Ruben Pio
{"title":"The C5a/C5aR1 axis promotes migration of tolerogenic dendritic cells to lymph nodes, impairing the anticancer immune response.","authors":"Yaiza Senent, Ana Remírez, David Repáraz, Diana Llopiz, Daiana P Celias, Cristina Sainz, Rodrigo Entrialgo-Cadierno, Lucia Suarez, Ana Rouzaut, Diego Alignani, Beatriz Tavira, John D Lambris, Trent M Woodruff, Carlos E de Andrea, Brian Ruffell, Pablo Sarobe, Daniel Ajona, Ruben Pio","doi":"10.1158/2326-6066.CIR-24-0250","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0250","url":null,"abstract":"<p><p>The precise mechanisms by which the complement system contributes to the establishment of an immunosuppressive tumor microenvironment (TME) and promotes tumor progression remain unclear. In this study, we investigated the expression and function of complement C5a receptor 1 (C5aR1) in human and mouse cancer-associated dendritic cells (DCs). First, we observed an overexpression of C5aR1 in tumor-infiltrating DCs, compared to DCs from blood or spleen. C5aR1 expression was restricted to type 2 conventional DCs (cDC2) and monocyte-derived DCs (moDCs), which displayed a tolerogenic phenotype capable of inhibiting T-cell activation and promoting tumor growth. C5aR1 engagement in DCs drove their migration from tumors to tumor-draining lymph nodes, where C5a levels were higher. We used this knowledge to optimize an anticancer therapy aimed at enhancing DC activity. In three syngeneic tumor models, C5aR1 inhibition significantly enhanced the efficacy of poly I:C, a Toll-like receptor 3 (TLR3) agonist, in combination with PD-1/PD-L1 blockade. The contribution of C5aR1 inhibition to the antitumor activity of the combination treatment relied on type 1 conventional DCs (cDC1s) and antigen-specific CD8+ T cells, required lymphocyte egress from secondary lymphoid organs, and was associated with an increase in interferon gamma (IFNγ) signaling. In conclusion, our study highlights the importance of the C5a/C5aR1 axis in the biology of cancer-associated DCs and provides compelling evidence for the therapeutic potential of modulating the complement system to enhance DC-mediated immune responses against tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicholas A Maskalenko, Sam Zahroun, Oxana Tsygankova, Nadia Anikeeva, Yuri Sykulev, Kerry S Campbell
{"title":"The FcγRIIIA (CD16) L48-H/R polymorphism enhances NK cell-mediated antibody-dependent cellular cytotoxicity by promoting serial killing.","authors":"Nicholas A Maskalenko, Sam Zahroun, Oxana Tsygankova, Nadia Anikeeva, Yuri Sykulev, Kerry S Campbell","doi":"10.1158/2326-6066.CIR-24-0384","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0384","url":null,"abstract":"<p><p>Many tumor-specific monoclonal antibody therapies stimulate antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells through FcγRIIIa (CD16). The efficacy of these ADCC-based immunotherapies is potentiated in patients with the common CD16 polymorphic variant F158-V that increases the binding affinity between the receptor and the IgG Fc domain. However, other CD16 variants are less well characterized. Here, we report that CD16 L48-H and L48-R variants both significantly enhance in vitro ADCC responses in primary NK cells and NK-92 cells. During ADCC responses, NK cells expressing CD16 48-H killed and disengaged from target cells faster than those expressing CD16 48-L, resulting in improved serial killing of tumor cells. We found that CD16 48-H also formed an immunological synapse with a more compact interface, as well as more robust intracellular calcium signaling and quicker polarization of cytolytic vesicles. The ADCC response observed occurs due to increased cytolytic signaling and target cell disengagement, which drives NK cell-mediated serial killing of tumor cells. The L48-H/R polymorphism has potential to benefit patient responses to cancer antibody therapies and may also potentiate anti-tumor ADCC responses if incorporated into adoptive NK cell therapeutic platforms.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jonas Lehmann, Martin Thelen, Christoph Kreer, Simon Schran, Maria A García-Marquez, Igor Cisic, Klara Siepmann, Elena M Hagen, Hans Nikolaus Caspar Eckel, Philipp Lohneis, Stephan Kruger, Stefan Boeck, Steffen Ormanns, Martina Rudelius, Jens Werner, Felix Popp, Florian Klein, Michael S von Bergwelt-Baildon, Christiane J Bruns, Alexander Quaas, Kerstin Wennhold, Hans A Schlößer
{"title":"Tertiary lymphoid structures in pancreatic cancer are structurally homologous, share gene expression patterns and B-cell clones with secondary lymphoid organs but show increased T-cell activation.","authors":"Jonas Lehmann, Martin Thelen, Christoph Kreer, Simon Schran, Maria A García-Marquez, Igor Cisic, Klara Siepmann, Elena M Hagen, Hans Nikolaus Caspar Eckel, Philipp Lohneis, Stephan Kruger, Stefan Boeck, Steffen Ormanns, Martina Rudelius, Jens Werner, Felix Popp, Florian Klein, Michael S von Bergwelt-Baildon, Christiane J Bruns, Alexander Quaas, Kerstin Wennhold, Hans A Schlößer","doi":"10.1158/2326-6066.CIR-24-0299","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0299","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLS) in cancer are considered ectopic hotspots for immune activation that are similar to lymphoid follicles in secondary lymphoid organs (SLO). This study elucidates shared and TLS/SLO-specific features in pancreatic ductal adenocarcinoma (PDAC). TLS abundance was related to superior survival and T-cell abundance in 110 treatment-naïve PDAC samples, underlining their clinical relevance. Immunofluorescence microscopy identified structural homologies between TLS and SLO. In RNA-expression analyses of laser-microdissected TLS and paired SLOs, we observed largely overlapping expression patterns of immune-related gene clusters, but distinct expression patterns of T-cell and complement-associated genes. Immune cells in TLS expressed essential markers of germinal center formation. Increased activation of tumor-draining lymph nodes in patients with high numbers of TLS highlights the relevance of these tumor-related structures to systemic immune response. In line with this, we identified an overlap of expanded B-cell receptor clonotypes in TLS and SLO, which suggests a vivid cross-talk between the two compartments. . We conclude that combined therapeutic approaches exploiting TLS-mediated antitumor immune responses may improve susceptibility of PDAC to immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Identification and phenotypic characterization of neoantigen-specific cytotoxic CD4+ T cells in endometrial cancer.","authors":"Minami Fusagawa, Serina Tokita, Kenji Murata, Tasuku Mariya, Mina Umemoto, Shintaro Sugita, Kazuhiko Matsuo, Yoshihiko Hirohashi, Tsuyoshi Saito, Takayuki Kanaseki, Toshihiko Torigoe","doi":"10.1158/2326-6066.CIR-24-0514","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0514","url":null,"abstract":"<p><p>Tumor-reactive CD4+ T cells often accumulate in the tumor microenvironment (TME) in human cancer, but their functions and roles in antitumor responses remain elusive. Here, we investigated the immunopeptidome of HLA class II-positive (HLA-II+) endometrial cancer with an inflamed TME using a proteogenomic approach. We identified HLA-II neoantigens, one of which induced polyclonal CD4+ tumor-infiltrating lymphocyte (TIL) responses. We then experimentally demonstrated that neoantigen-specific CD4+ TILs lyse target cells in an HLA-II-dependent manner. Single cell transcriptomic analysis of the TME coupled with T-cell receptor (TCR) sequencing revealed the presence of CD4+ T-cell clusters characterized by CXCL13 expression. The CXCL13+ clusters contained two subclusters with distinct cytotoxic gene expression patterns. The identified neoantigen-specific CD4+ T cells were found exclusively in one of the CXCL13+ subclusters characterized by granzyme B and CCL5 expression. These results demonstrate the involvement of tumor-reactive CD4+ T cells with cytotoxic function in immune surveillance of endometrial cancer and reveal their transcriptomic signature.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michelle C Buri, Mohamed R Shoeb, Aleksandr Bykov, Peter Repiscak, Hayeon Baik, Alma Dupanovic, Faith O David, Boris Kovacic, Faith Hall-Glenn, Sara Dopa, Jos Urbanus, Lisa Sippl, Susanne Stofner, Dominik Emminger, Jason Cosgrove, Dagmar Schinnerl, Anna R Poetsch, Manfred Lehner, Xaver Koenig, Leila Perie, Ton N Schumacher, Dagmar Gotthardt, Florian Halbritter, Eva M Putz
{"title":"Natural killer cell-mediated cytotoxicity shapes the clonal evolution of B cell leukaemia.","authors":"Michelle C Buri, Mohamed R Shoeb, Aleksandr Bykov, Peter Repiscak, Hayeon Baik, Alma Dupanovic, Faith O David, Boris Kovacic, Faith Hall-Glenn, Sara Dopa, Jos Urbanus, Lisa Sippl, Susanne Stofner, Dominik Emminger, Jason Cosgrove, Dagmar Schinnerl, Anna R Poetsch, Manfred Lehner, Xaver Koenig, Leila Perie, Ton N Schumacher, Dagmar Gotthardt, Florian Halbritter, Eva M Putz","doi":"10.1158/2326-6066.CIR-24-0189","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0189","url":null,"abstract":"<p><p>The term cancer immunoediting describes the dual role by which the immune system can suppress and promote tumour growth and is divided into three phases: elimination, equilibrium and escape. The role of NK cells has mainly been attributed to the elimination phase. Here we show that NK cells play a role in all three phases of cancer immunoediting. Extended co-culturing of DNA barcoded mouse BCR/ABLp185+ B-cell acute lymphoblastic leukaemia (B-ALL) cells with NK cells allowed for a quantitative measure of NK cell-mediated immunoediting. Although most tumour cell clones were efficiently eliminated by NK cells, a certain fraction of tumour cells harboured an intrinsic primary resistance. Furthermore, DNA barcoding revealed tumour cell clones with secondary resistance, which stochastically acquired resistance to NK cells. NK cell-mediated cytotoxicity put a selective pressure on B-ALL cells, which led to an outgrowth of primary and secondary resistant tumour cell clones, which were characterised by an IFN-γ signature. Besides well-known regulators of immune evasion, our analysis of NK cell-resistant tumour cells revealed the upregulation of genes, including Ly6a, which we found to promote leukaemic-cell resistance to NK cells. Translation of our findings to the human system showed that high expression of LY6E on tumour cells impaired their physical interaction with NK cells and led to worse prognosis in leukaemia patients. Our results demonstrate that tumour cells are actively edited by NK cells during the equilibrium phase and use different avenues to escape NK cell-mediated eradication.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jaemoon Koh, Dongjoo Lee, Sehui Kim, Seung Geun Song, Bogyeong Han, Hyein Jeong, Young A Kim, Bhumsuk Keam, Se-Hoon Lee, Kwangsoo Kim, Yoon Kyung Jeon, Doo Hyun Chung
{"title":"Spatially Resolved Whole-Transcriptomic and Proteomic Profiling of Lung Cancer and Its Immune Microenvironment According to PD-L1 Expression.","authors":"Jaemoon Koh, Dongjoo Lee, Sehui Kim, Seung Geun Song, Bogyeong Han, Hyein Jeong, Young A Kim, Bhumsuk Keam, Se-Hoon Lee, Kwangsoo Kim, Yoon Kyung Jeon, Doo Hyun Chung","doi":"10.1158/2326-6066.CIR-24-0071","DOIUrl":"10.1158/2326-6066.CIR-24-0071","url":null,"abstract":"<p><p>The expression of PD-L1 on tumor cells (TC) is used as an immunotherapy biomarker in lung cancer, but heterogeneous intratumoral expression is often observed. To better understand heterogeneity in the lung cancer tumor microenvironment, we performed proteomic and whole-transcriptomic digital spatial profiling analyses of TCs and immune cells (IC) in spatially matched areas based on tumor PD-L1 expression and the status of the immune microenvironment. We validated our findings using IHC, data from The Cancer Genome Atlas, and immunotherapy cohorts. ICs in areas with high PD-L1 expression on TCs showed more features, indicative of immunosuppression and exhaustion, than ICs in areas with low PD-L1 expression on TCs. TCs highly expressing PD-L1 within immune-inflamed areas showed upregulation of proinflammatory processes, whereas TCs highly expressing PD-L1 within immune-deficient areas showed upregulation of various metabolic processes. Using differentially expressed genes of TCs between the immune-inflamed and immune-deficient areas, we identified a prognostic gene signature for lung cancer. In addition, we found that a high ratio of CD8+ cells to M2 macrophages predicted favorable outcomes in patients with PD-L1-expressing lung cancer after immune checkpoint inhibitor therapy. Overall, this study demonstrates that TCs and ICs have distinct spatial features within the lung tumor microenvironment that are related to tumor PD-L1 expression and IC infiltration.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1753-1764"},"PeriodicalIF":8.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"BTN2A1: A Novel Target to Boost Tumor Killing Capacity of Human γδ T Cells.","authors":"Dieter Kabelitz","doi":"10.1158/2326-6066.CIR-24-0925","DOIUrl":"10.1158/2326-6066.CIR-24-0925","url":null,"abstract":"<p><p>γδ T cells have recently raised great interest as effector cells in cancer immunotherapy because of their HLA-independent mode of action and their broad tumor reactivity. To translate the application of γδ T cells into clinically effective immunotherapies, specific tumor targeting and/or boosting of γδ T-cell activation in vivo seem to be a critical step. In this issue, Le Floch and colleagues report a new strategy for enabling γδ T cells to be specifically activated to kill acute lymphoblastic leukemia cells and solid tumor cells using agonistic BTN2A1 antibodies. See related article by Le Floch et al., p. 1677.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1662"},"PeriodicalIF":8.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bu Gyeom Kim, Bo Ram Kim, Dae Yeong Kim, Woo Young Kim, Sanghee Kang, Sun Il Lee, Sang Cheul Oh
{"title":"Cannabidiol Enhances Atezolizumab Efficacy by Upregulating PD-L1 Expression via the cGAS-STING Pathway in Triple-Negative Breast Cancer Cells.","authors":"Bu Gyeom Kim, Bo Ram Kim, Dae Yeong Kim, Woo Young Kim, Sanghee Kang, Sun Il Lee, Sang Cheul Oh","doi":"10.1158/2326-6066.CIR-23-0902","DOIUrl":"10.1158/2326-6066.CIR-23-0902","url":null,"abstract":"<p><p>The treatment of patients with triple-negative breast cancer (TNBC) relies on cytotoxic therapy. Currently, atezolizumab and chemotherapy can be combined in patients with TNBC. However, this approach is not effective for all patients, with many tumors showing low responsiveness to atezolizumab. As there is a lack of alternative treatment options, new anticancer drugs are urgently needed to enhance atezolizumab activity against TNBC. Recent strategies have focused on regulating the expression of programmed cell death ligand 1 (PD-L1) or enhancing immune response activation by combining anticancer drugs with immune checkpoint inhibitors. Cannabidiol (CBD), a cannabinoid component derived from the cannabis plant, has been reported to have anticancer therapeutic potential because of its capacity to induce apoptotic cell death in tumor cells while avoiding cytotoxicity in normal cells. Previous studies have demonstrated the effects of CBD on apoptosis in various cancer cell types. However, the potential role of CBD as an immune modulator in the regulation of PD-L1 expression and anticancer immune responses remains to be explored. In this study, we found that CBD stimulated PD-L1 expression in TNBC cells and that this occurred downstream of CBD-mediated cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway activation. Taken together, we have demonstrated that the combination of CBD and anti-PD-L1 enhances the anticancer immune responses in in vitro and in vivo experiments. Our findings identified the mechanism of PD-L1 regulation by CBD in TNBC cells and suggested that CBD could be a potential candidate for the development of new combinatorial strategies with immune checkpoint inhibitors in patients with TNBC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1796-1807"},"PeriodicalIF":8.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"CAR T Cells Engineered to Secrete IFNκ Induce Tumor Ferroptosis via an IFNAR/STAT1/ACSL4 Axis.","authors":"Yaoxin Gao, Shasha Liu, Yifan Huang, Hui Wang, Yuyu Zhao, Xuyang Cui, Yajing Peng, Feng Li, Yi Zhang","doi":"10.1158/2326-6066.CIR-24-0130","DOIUrl":"10.1158/2326-6066.CIR-24-0130","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of cell death that influences cancer immunity. Therapeutic modulation of ferroptosis is considered a potential strategy to enhance the efficacy of other cancer therapies, including immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy. In this study, we demonstrated that IFNκ influenced the induction of ferroptosis. IFNκ could enhance the sensitivity of tumor cells to ferroptosis induced by the small molecule compound erastin and the polyunsaturated fatty acid arachidonic acid. Mechanistically, IFNκ in combination with arachidonic acid induced immunogenic tumor ferroptosis via an IFNAR/STAT1/ACSL4 axis. Moreover, CAR T cells engineered to express IFNκ showed increased antitumor efficiency against H460 cells (antigen positive) and H322 cells (antigen-negative) both in vitro and in vivo. We conclude that IFNκ is a potential cytokine that could be harnessed to enhance the antitumor function of CAR T cells by inducing tumor ferroptosis.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1691-1702"},"PeriodicalIF":8.1,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11612617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
