Cancer immunology research最新文献

{"title":"The spatial organization of cDC1 with CD8+ T cells is critical for the response to immune checkpoint inhibitors in melanoma patients.","authors":"Elisa Gobbini, Margaux Hubert, Anne-Claire Doffin, Anais Eberhardt, Léo Hermet, Danlin Li, Pierre Duplouye, Sarah Ghamry-Barrin, Justine Berthet, Valentin Benboubker, Maxime Grimont, Candice Sakref, Jimmy Perrot, Garance Tondeur, Olivier Harou, Jonathan Lopez, Bertrand Dubois, Stephane Dalle, Christophe Caux, Julie Caramel, Jenny Valladeau-Guilemond","doi":"10.1158/2326-6066.CIR-24-0421","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0421","url":null,"abstract":"<p><p>Dendritic cells (DCs) are promising targets for cancer immunotherapies because of their central role in the initiation and control of immune responses. The rare cDC1 population is of particular interest because of its remarkable ability to cross-present antigens (Ag) to CD8+ T cells, to promote Th1 cell polarization and NK cell activation and recruitment. However, the spatial organization and specific functions of cDC1s in response to immunotherapy remain to be clearly characterized in human tumors. Here, we implemented a multiplexed immunofluorescence analysis pipeline coupled with computational image analysis to determine the spatial organization of the cDC1 subset in a cohort of skin lesions from advanced melanoma patients treated with immune checkpoint inhibitors (ICI). For this, we performed a whole-slide image analysis of cDC1 infiltration and distribution as well as their spatial interactions with key immune partners such as CD8+ T cells and pDC according to the response of patients to ICI. We also analyzed LAMP3+-DC, which correspond to a mature subset of tumor-infiltrating DCs. Distance and cell network analyses demonstrated that cDC1s exhibited a scattered distribution compared to tumor-infiltrating pDCs and LAMP3+-DCs, which were preferentially organized in dense areas with high homotypic connections. Interestingly, the proximity and interactions between CD8+ T cells and cDC1s were positively associated with the response to ICI. In conclusion, our study unravels the complex spatial organization of cDC1s and their interactions with CD8+ T cells in melanoma patient lesions, shedding light on their pivotal role in shaping the response to ICI.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945097","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":"Endogenous CD4 T cells that recognize ALK and the NPM1::ALK fusion protein can be expanded from human peripheral blood.","authors":"Serena Stadler, Rafael B Blasco, Vijay Kumar Singh, Christine Damm-Welk, Amin Ben-Hamza, Carlotta Welters, Leo Hansmann, Roberto Chiarle, Wilhelm Wossmann","doi":"10.1158/2326-6066.CIR-24-0445","DOIUrl":"10.1158/2326-6066.CIR-24-0445","url":null,"abstract":"<p><p>Anaplastic lymphoma kinase (ALK)-fusion proteins resulting from chromosomal rearrangements are promising targets for cancer immunotherapy. While ALK-specific CD8+ T cells and epitopes presented on MHC class I have been identified in patients with ALK-positive malignancies, little is known about ALK-specific CD4+ T cells. We screened peripheral blood of ten ALK-positive anaplastic large cell lymphoma (ALK+ALCL) patients in remission and six healthy donors for CD4+ T-cell responses to the whole ALK-fusion protein, nucleophosmin (NPM1)::ALK. ALK-specific CD4+ T cells were detected in 15 individuals after stimulation with autologous dendritic cells pulsed with long-overlapping ALK peptide pools. CD4+ T-cell epitopes were predominantly located within three specific regions (p102-188, p257-356, p593-680) in the ALK portion of the fusion protein. We detected CD4+ T cells in one patient that recognized the NPM1::ALK fusion neoepitope and identified a corresponding T-cell receptor (TCR) by TCR single-cell sequencing. The NPM1::ALK fusion-specific TCR was HLA-DR13 restricted and conferred antigen specificity when expressed in a TCR- reporter cell line (58--). Together, our data provide evidence of ALK-specific CD4+ T cells in human peripheral blood, describe target epitopes in patients and support the consideration of CD4+ T cells in the development of ALK-specific immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945088","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":"Trabectedin enhances the antitumor effects of IL-12 in triple-negative breast cancer.","authors":"Emily Schwarz, Himanshu Savardekar, Sara Zelinskas, Abigail Mouse, Gabriella Lapurga, Justin Lyberger, Adithe Rivaldi, Emily M Ringwalt, Katherine E Miller, Lianbo Yu, Gregory K Behbehani, Timothy P Cripe, William E Carson","doi":"10.1158/2326-6066.CIR-24-0775","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0775","url":null,"abstract":"<p><p>Interleukin-12 (IL-12) is a potent NK cell-stimulating cytokine, but the presence of immunosuppressive myeloid cells such as myeloid-derived suppressor cells (MDSC) can inhibit IL 12-induced NK-cell cytotoxicity. Thus, we hypothesized that trabectedin, a myeloid cell-depleting agent, would improve the efficacy of IL-12 in triple-negative breast cancer (TNBC). In vitro treatment of healthy donor NK cells with trabectedin increased expression of the activation marker CD69 and mRNA expression of T BET (Tbx21), the cytotoxic ligands TRAIL (TNFSF10) and Fas ligand (FASLG) and the dendritic cell (DC)-recruiting chemokine lymphotactin (XCL1). The combination of IL-12 and trabectedin increased NK-cell cytotoxicity, activation and production of IFN-γ, TNF-α and granzyme B in the presence of human TNBC cells. Treatment of 4T1 and EMT6 tumor-bearing mice with IL-12 and trabectedin led to a significant reduction in tumor burden compared to single-agent controls, and the highest levels of plasma IFN-γ, intratumoral CD8+ T cells and conventional type 1 DC. MDSC and M2-like macrophages were significantly decreased with combination therapy. NK-cell depletion abrogated the effects of combination therapy, as did elimination of CD8+ T cells. NK-cell depletion led to lower levels of the NK cell-derived chemokine CCL5 and the DC-derived chemokine CXCL10, higher tumor burden, and decreased intratumoral CD8+ T cells. IL 12 and trabectedin also significantly enhanced the response of TNBC to anti-PD-L1 therapy. These data suggest that MDSC depletion augments the ability of IL-12-activated NK cells to drive the infiltration of DC and CD8+ T cells into TNBC for an antitumor effect.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945100","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":"NI-3201 Is a Bispecific Antibody Mediating PD-L1-Dependent CD28 Co-stimulation on T Cells for Enhanced Tumor Control.","authors":"Sara Majocchi, Pauline Lloveras, Lise Nouveau, Margaux Legrand, Alizee Viandier, Pauline Malinge, Maud Charreton, Cecile Raymond, Emily A Pace, Bjorn L Millard, L Anders Svensson, Vinardas Kelpšas, Nadia Anceriz, Susana Salgado-Pires, Bruno Daubeuf, Giovanni Magistrelli, Franck Gueneau, Valéry Moine, Krzysztof Masternak, Limin Shang, Nicolas Fischer, Walter G Ferlin","doi":"10.1158/2326-6066.CIR-24-0298","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0298","url":null,"abstract":"<p><p>Despite advances in cancer immunotherapy, such as targeting the PD-1/PD-L1 axis, a substantial number of patients harbor tumors that are resistant or relapse. Selective engagement of T-cell co-stimulatory molecules with bispecific antibodies may offer novel therapeutic options by enhancing signal 1-driven activation occurring via T-cell receptor engagement. In this study, we report the development and preclinical characterization of NI-3201, a PD-L1×CD28 bispecific antibody generated on the κλ-body platform that was designed to promote T-cell activity and antitumor function through a dual mechanism of action. We confirmed that NI-3201 blocks the PD-L1/PD-1 immune checkpoint pathway and conditionally provides T-cell co-stimulation via CD28 (signal 2) when engaging PD-L1+ tumors or immune cells. In systems with signal 1-primed T cells, NI-3201 enhanced potent effector functionality: in vitro through antigen-specific recall assays with cytomegalovirus-specific T cells and in vivo by inducing tumor regression and immunologic memory in tumor-associated antigen-expressing MC38 syngeneic mouse models. When T-cell engagers were used to provide synthetic signal 1, the combination with NI-3201 resulted in synergistic T cell-dependent cytotoxicity and potent antitumor activity in two humanized mouse tumor models. Nonhuman primate safety assessments showed favorable tolerability and pharmacokinetics at pharmacologically active doses. Quantitative systems pharmacology modeling predicted that NI-3201 exposure results in antitumor activity in patients, but this remains to be investigated. Overall, this study suggests that by combining PD-L1 blockade with safe and effective CD28 co-stimulation, NI-3201 has the potential to improve cancer immunotherapy outcomes, and the clinical development of NI-3201 for PD-L1+ solid tumors is planned.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"OF1-OF19"},"PeriodicalIF":8.1,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930623","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":"Lung cancer-intrinsic SOX2 expression mediates resistance to checkpoint blockade therapy by inducing Treg cell-dependent CD8+ T-cell exclusion.","authors":"Elen Torres-Mejia, Sally Weng, Charles A Whittaker, Kim B Nguyen, Ellen Duong, Leon Yim, Stefani Spranger","doi":"10.1158/2326-6066.CIR-24-0184","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0184","url":null,"abstract":"<p><p>Tumor cell-intrinsic signaling pathways can drastically affect the tumor immune microenvironment, promoting tumor progression and resistance to immunotherapy by excluding immune-cell populations from the tumor. Several tumor cell-intrinsic pathways have been reported to modulate myeloid-cell and T-cell infiltration creating \"cold\" tumors. However, clinical evidence suggests that excluding cytotoxic T cells from the tumor core also mediates immune evasion. Here, we find that tumor cell-intrinsic SOX2 signaling in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. Mechanistically, tumor cell-intrinsic SOX2 expression upregulates CCL2 in tumor cells, resulting in increased recruitment of regulatory T cells. CD8+ T-cell exclusion depended on regulatory T cell-mediated suppression of tumor vasculature. Depleting tumor-infiltrating regulatory T cells via Glucocorticoid-Induced TNFR-Related protein (GITR) restored CD8+ T-cell infiltration and, when combined with checkpoint blockade therapy, reduced tumor growth. These results show that tumor cell-intrinsic SOX2 expression in lung cancer serves as a mechanism of immunotherapy resistance and provide evidence to support future studies investigating whether NSCLC patients with SOX2-dependent CD8+ T-cell exclusion would benefit from the depletion of GITR+ Tregs.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913831","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":"Spatial Organization of Macrophages in CTL Rich Hepatocellular Carcinoma Influences CTL Antitumor Activity.","authors":"Yulan Weng, Lu Wang, Yuting Wang, Junyu Xu, Xiaoli Fan, Shufeng Luo, Qiaomin Hua, Jing Xu, Gaoteng Liu, Kai-Bo Zhao, Chang-An Zhao, Dong-Ming Kuang, Chong Wu, Limin Zheng","doi":"10.1158/2326-6066.CIR-24-0589","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0589","url":null,"abstract":"<p><p>Despite the pivotal role of cytotoxic T lymphocytes (CTLs) in anti-tumor immunity, a substantial proportion of CTL-rich hepatocellular carcinoma (HCC) patients experience early relapse or immunotherapy resistance. However, spatial immune variations impacting the heterogeneous clinical outcomes of CTL-rich HCCs remain poorly understood. Here, we compared the single-cell and spatial landscapes of 20 CTL-rich HCCs with distinct prognoses using multiplexed in situ staining and validated the prognostic value of myeloid spatial patterns in a cohort of 386 patients. Random forest and Cox regression models identified macrophage aggregation as a distinctive spatial pattern characterizing a subset of CTL-rich HCCs with an immunosuppressive microenvironment and poor prognosis. Integrated analysis of single-cell and spatial transcriptomics, combined with in situ staining validation, revealed that spatial aggregation enhanced pro-tumoral macrophage reprogramming in HCCs, marked by lipid metabolism orientation, M2-like polarization, and increased adjacent CTL exhaustion. This spatial effect on macrophage reprogramming was replicated in HCC-conditioned human macrophage cultures, which showed an enhanced capability to suppress CTLs. Notably, increased macrophage aggregation was associated with higher response rates to anti-PD-1 immunotherapy. These findings suggest that the spatial distribution of macrophages is a biomarker of their functional diversities and microenvironment status, which holds prognostic and therapeutic implications.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913843","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":"Profiling Multiple CD8+ T-Cell Functional Dimensions Enhances Breast Cancer Immune Assessment.","authors":"Zhuozhi Liang, Shunrong Li, Zhilong Pan, Yuanqiang Duan, Qian Ouyang, Liling Zhu, Erwei Song, Kai Chen","doi":"10.1158/2326-6066.CIR-24-0235","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0235","url":null,"abstract":"<p><p>CD8+ T-cell abundance is insufficient to assess antitumor immunity and shows poor performance in predicting breast cancer prognosis and immunotherapy response, presumably owing to the complexity of CD8+ T-cell functionalities. While single-cell RNA sequencing (scRNA-seq) can dissect the multifaceted functions of CD8+ T cells for better immune assessment, its clinical application is limited. Herein, we developed bulk RNA-seq-based FuncDimen models from integrative analysis of scRNA-seq and matched bulk RNA-seq data, to evaluate CD8+ T-cell functionalities across 5 dimensions: tumor reactivity, cytotoxicity, IFN-γ secretion, proliferation, and apoptosis. The FuncDimen models quantifying different functional dimensions of CD8+ T cells were validated in our breast cancer cohort and external databases using immunofluorescence and imaging mass cytometry. We calculated the FuncAggre score by weighted aggregation of all 5 FuncDimen models to encapsulate the overall antitumor immunity. In our breast cancer cohort and external databases, FuncAggre score demonstrated superior predictive performance for breast cancer prognosis (time-dependent area under the curve [AUC]: 0.56-0.70) and immunotherapy response (AUC: 0.71-0.83) over other immune biomarkers, regardless of the breast cancer molecular subtype. Together, the FuncDimen models offer a refined assessment of antitumor immunity mediated by CD8+ T cells in the clinic, enhancing prognostic prediction and aiding personalized immunotherapy in breast cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881448","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":"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}

{"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}

{"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}