Cancer immunology research最新文献

{"title":"Adaptive NK Cells Exhibit Tumor-Specific Immune Memory and Cytotoxicity in Ovarian Cancer.","authors":"Yizhe Sun, Andrea Rodgers Furones, Okan Gultekin, Shruti Khare, Shi Yong Neo, Wenyang Shi, Lidia Moyano-Galceran, Kong-Peng Lam, Ramanuj Dasgupta, Jonas Fuxe, Sahar Salehi, Kaisa Lehti, Dhifaf Sarhan","doi":"10.1158/2326-6066.CIR-24-0852","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0852","url":null,"abstract":"<p><p>Adaptive Natural Killer (aNK) cells have emerged as a subset of NK cells with memory-like properties and specific cytotoxicity, offering promising therapeutic potential in cancer immunotherapy. In this study, we explored the role of aNK cells in high-grade serous ovarian cancer (HGSOC), focusing on their ability to establish tumor-specific immune memory and effectively target autologous tumors. Through a combination of in silico, in vitro, and ex vivo approaches, we demonstrated that aNK cells, in contrast to conventional NK (cNK) cells, exhibit recall responses, specific cytotoxicity, and preferential infiltration into the tumor microenvironment (TME). Our data revealed that aNK cells interact with dendritic cells (DCs) within the TME via the HLA-E/NKG2C axis and CXCR2 signaling, contributing to their memory formation and tumor-targeting capabilities. These findings suggest that aNK cells could serve as potent agents in NK cell-based immunotherapies, particularly in solid tumors like HGSOC, where they resist immunosuppressive signals and maintain robust anti-tumor activity. This study provides new insights into the adaptive-like properties of aNK cells, underscoring their potential for advancing cancer immunotherapy strategies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978841","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":"A dendritic cell-like transition of T cells is associated with spontaneous remission of adult T-cell leukemia-lymphoma.","authors":"Miho Watanabe, Jun-Ichirou Yasunaga, Osama Hussein, Azusa Tanaka, Takafumi Shichijo, Mikiko Izaki, Yuki Okamoto, Yoshihiro Komohara, Masao Matsuoka","doi":"10.1158/2326-6066.CIR-24-0306","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0306","url":null,"abstract":"<p><p>Spontaneous remission in patients with various cancers has been reported. Some patients with adult T-cell leukemia-lymphoma (ATL), have experienced spontaneous remission, although mechanisms for this remain unknown. In this study, we analyzed ATL cells and human T-cell leukemia virus type 1 (HTLV-1) infected cells using Cytometry by Time-Of-Flight mass spectrometry (CyTOF). We observed a small number (less than 5% on average) of ATL cells and HTLV-1 infected cells expressed CD14 and other dendritic cell (DC) associated molecules such as CD1c, CD11b, CD11c, and CD141. Single cell analysis revealed that these T cells expressing DC markers also contained rearranged TCR genes, indicating that these cells are indeed derived from T cells. In an ATL patient who entered into remission after contracting coronavirus disease 2019 (COVID-19), the number of DC-like T cells increased, and ELISPOT assay detected CTLs against Tax in accordance with regression of ATL. These findings suggest that DC-like ATL cells acquire antigen-presenting capability, and induce spontaneous remission through enhanced immunity to the virus. Specifically, in an ATL cell line, enforced expression of IRF8 and PU.1 in addition to endogenous BATF3 expression increased CD86 expression and enabled the cells to present Tax peptide antigens to T cells. Collectively, these data indicate that ATL cells acquire antigen-presenting activity when IRF8, PU.1 and BATF3 are expressed, suggesting that transition of a subset of T cells to DC-like T cells can induce immune responses to viral antigens, resulting in spontaneous remission. Thus, the transition of T cells to DC-like T cells is a unique mechanism for spontaneous remission in ATL.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977747","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":"NEDDylation regulates CD8+ T cell metabolism and anti-tumor immunity.","authors":"Borja Jimenez-Lasheras, Paloma Velasco-Beltrán, Leire Egia-Mendikute, Lorena Pérez-Gutiérrez, So Young Lee, Ander de Blas, Ana García Del Río, Samanta Romina Zanetti, Asier Antoñana-Vildosola, Adrián Barreira-Manrique, Alexandre Bosch, Jone Etxaniz Díaz de Durana, Endika Prieto-Fernández, Marina Serrano-Maciá, Naroa Goikoetxea-Usandizaga, Mikel Azkargorta, Felix Elortza, Thomas Gruber, Sebastian Peer, Gottfried Baier, Ashwin Woodhoo, María Luz Martínez-Chantar, Asis Palazon","doi":"10.1158/2326-6066.CIR-24-0127","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0127","url":null,"abstract":"<p><p>NEDDylation is a post-translational modification whereby the ubiquitin-like molecule NEDD8 is attached to protein substrates in a process dependent on NEDD8 activating enzyme regulatory subunit (NAE1). NEDDylation is emerging as a regulator of cancer biology, but its precise role in antitumor immunity has not been thoroughly characterized. Here, we study the impact of NEDDylation in CD8+ T cell-mediated antitumor responses. Analysis of publicly available single-cell RNA sequencing databases revealed that CD8+ tumor-infiltrating lymphocytes (TILs) showed increased expression of NEDD8 during their differentiation into effector memory cells. In vitro activation of mouse and human CD8+ T cells drove the upregulation of the NEDDylation enzymatic pathway, resulting in an enrichment of NEDDylated proteins. In vivo tumor challenge assays demonstrated that CD8+ T cells lacking NAE1 (NAE1-KO) exhibited reduced antitumor capability and a less activated phenotype with compromised differentiation into effector cells. Upregulating NEDDylation by knocking out deNEDDylase sentrin-specific protease 8 (SENP8) increased the in vitro cytotoxic capability of CD8+ CAR T cells. In addition, LC MS/MS proteomic analyses of NAE1-KO CD8+ T cells and CD8+ T cells treated with the NEDDylation inhibitor MLN4924, showed a pronounced impairment in metabolic pathways, including glycolysis and oxidative phosphorylation. In this context, we validated lactate dehydrogenase A, α-enolase and hexokinase 1, which are relevant glycolytic enzymes, as NEDD8 targets. In line with this, NEDDylation-deficient CD8+ T cells demonstrated reduced transcription, protein expression and enzymatic activity of lactate dehydrogenase. In summary, we uncover NEDDylation as a critical regulator of CD8+ T cell-mediated antitumor immunity.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989945","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":"Deep immune phenotyping reveals distinct immunopathogenesis in checkpoint inhibitor-induced colitis compared to ulcerative colitis.","authors":"Giulia Pesch, Ignazio Piseddu, Jan Gaertig, Nora Kramer, Rafaela Kramer, Thomas U Schulz, Maximilian Zwiebel, Stephan Ledderose, Jimmy Retzlaff, Markus Eckstein, Georg Schett, Claudia Kammerbauer, Christina Schmitt, Joerg Kumbrink, Michael Erdmann, Wolfgang Kruis, Michael Dougan, Julia Mayerle, Lars E French, Julio Vera, Thierry M Nordmann, Matthias Mann, Frederick Klauschen, David Anz, Lucie Heinzerling","doi":"10.1158/2326-6066.CIR-24-0387","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0387","url":null,"abstract":"<p><p>Although initially assumed to be similar, immune checkpoint inhibitor (ICI)-induced autoimmunity can differ from spontaneous autoimmune disease regarding clinical presentation, pathogenesis and therapy. Despite limited pathogenetic understanding, ICI-induced colitis (irColitis), a common adverse event during ICI therapy, is treated analogously to its autoimmune counterpart, ulcerative colitis (UC). Thus, there is a tremendous need to characterize immunophenotypes in both forms of colonic inflammation to ultimately identify specific therapeutic strategies. In a multicenter study, local and systemic immunophenotypes of patients with irColitis were compared to patients with UC. Colonic mucosa, patient serum and peripheral blood mononuclear cells (PBMC) of 20 patients with irColitis, 15 patients with UC and 25 patients receiving ICI without toxicity were investigated. Immunophenotyping was performed using gene expression analyses of mucosal samples and PBMC, serum proteomics and flow cytometry-based PBMC analysis. Mucosal gene expression analysis revealed higher expression of B cell- and TNF signaling-related genes in UC, whereas irColitis mucosa showed an upregulation of genes associated with effector T cell responses and interferon signaling. Immunophenotyping of PBMC demonstrated increased activation and differentiation of T cells and higher expression of exhaustion markers in irColitis compared to UC. In contrast, dendritic cells (DC) and B cells demonstrated increased markers of activation in patients with UC. Taken together, irColitis is characterized by T cell-associated immunity, whereas B cell- and DC-mediated immune responses and TNF signaling are more important for UC immunopathogenesis. These observations could help identify more specific and efficient treatment strategies for irColitis.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978983","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":"Targeting cancer-associated glycosylation for adoptive T cell therapy of solid tumors.","authors":"Andreas Zingg, Reto Ritschard, Helen Thut, Mélanie Buchi, Andreas Holbro, Anton Oseledchyk, Viola Heinzelmann, Andreas Buser, Mascha Binder, Alfred Zippelius, Natalia Rodrigues Mantuano, Matthias Matter, Heinz Läubli","doi":"10.1158/2326-6066.CIR-24-1050","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1050","url":null,"abstract":"<p><p>CAR T-cell therapy has improved outcomes for patients with chemotherapy-resistant B-cell malignancies. However, CAR T-cell treatment of patients with solid cancers has been more difficult, in part because of the heterogeneous expression of tumor-specific cell surface antigens. Here, we describe the generation of a fully human CAR targeting altered glycosylation in secretory epithelial cancers. The expression of the target antigen - the truncated, sialylated O-glycan sialyl-Thomsen-Nouveau antigen (STn) - was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastro-intestinal cancers including pancreatic cancers and in gynecological cancers, in particular ovarian and endometrial tumors. T cells expressing anti-STn CAR were tested in vitro and in vivo. Anti-STn CAR T cells showed activity in mouse models as well as in assays with primary ovarian cancer samples. No considerable toxicity was observed in mouse models, although some intraluminal expression of STn was found in gastro-intestinal mouse tissue. Taken together, this fully human anti-STn CAR construct shows promising activity in preclinical tumor models supporting its further evaluation in early clinical trials.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962077","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":"First-in-Human Clinical Trial of Vaccination with WDVAX, a Dendritic Cell Activating Scaffold Incorporating Autologous Tumor Cell Lysate, in Metastatic Melanoma Patients.","authors":"F Stephen Hodi, Anita Giobbie-Hurder, Kwasi Adu-Berchie, Srin Ranasinghe, Ana Lako, Mariano Severgnini, Emily M Thrash, Jason L Weirather, Joanna Baginska, Michael P Manos, Edward J Doherty, Alexander Stafford, Heather Daley, Jerome Ritz, Patrick A Ott, Kathleen L Pfaff, Scott J Rodig, Charles H Yoon, Glenn Dranoff, David J Mooney","doi":"10.1158/2326-6066.CIR-24-0333","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0333","url":null,"abstract":"<p><p>The optimal means to prime for effective anti-tumor immunity in a cancer patient remains elusive in the current era of checkpoint blockade. Crafting a strategy to amplify CD8+ T cells while blocking regulatory cells should increase immunotherapy efficacy. Biomaterial carriers have been demonstrated in preclinical studies to amplify the effects of immunomodulatory agents, synergistically integrate the effects of different agents, and concentrate and manipulate immune cells in vivo. In this phase I trial in patients with metastatic melanoma, the cytokine GM-CSF and the innate TLR9 agonist CpG oligonucleotide were admixed with autologous tumor lysate onto a microporous poly-lactide-co-glycolide (PLG) matrix polymer scaffold that achieves precise control over the spatial and temporal release of immunostimulatory agents in vivo. This materials system served as a physical antigen-presenting structure for which dendritic cells and other immune-stimulating cells are recruited and activated (WDVAX). In this first clinical trial of a macroscale biomaterial-based vaccine, WDVAX treatment was found to be feasible and induced immune activation in melanoma patients.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143983395","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 TRIB2-DNMT1 pathway generates an immune cold microenvironment in glioblastoma and its inhibition promotes immunotherapy.","authors":"Berta Segura-Collar, Blanca Cómitre-Mariano, Denisse Alcivar López, Lucia Modejar-Ruescas, Marta Caamaño-Moreno, Elena Tovar Ambel, Javier Gutierrez-Martin, Marina Garín, Oscar Toldos, Aurelio Hernández-Laín, Ricardo Gargini, Juan M Sepúlveda","doi":"10.1158/2326-6066.CIR-24-0807","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0807","url":null,"abstract":"<p><p>The lack of response of glioblastoma (GBM) to immunotherapy is closely related to the limited number of T cells in the tumor microenvironment (TME). However, it is still not known why GBM is characterized by an immune-cold TME with reduced CD8+ T-cell infiltration when there is substantial myeloid cell infiltration and a substantial alteration of the blood-brain barrier. The aim of this study was to identify regulators of low CD8+ T-cell infiltration in GBM. Using transcriptomic screening, we found that TRIB2 is a regulator of the immune-cold microenvironment characteristic of GBM. Further analysis of a cohort of 114 brain tumors with immunohistochemistry, RNA-sequencing and quantitative real-time PCR, showed that TRIB2 inhibited the transcription of genes involved in antigen presentation by the tumor cells and of genes involved in T-cell recruitment by modulating expression of methylation regulators, in particular DNMT1. Further, we observed 75% survival after TRIB2 inhibition in murine glioma models and showed transcriptomic reprogramming by Decitabine of genes involved in the processes described above. In our patient-derived tumor fragments assay we observed a consistent generalized response to decitabine, suggesting that DNMT1 inhibition could be a promising therapeutic strategy for GBM.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143964322","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 Spatial Organization of cDC1 with CD8+ T Cells is Critical for the Response to Immune Checkpoint Inhibitors in Patients with Melanoma.","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":"10.1158/2326-6066.CIR-24-0421","url":null,"abstract":"<p><p>Dendritic cells (DC) are promising targets for cancer immunotherapies because of their central role in the initiation and control of immune responses. The type 1 conventional DC (cDC1) population is of particular interest because of its ability to cross-present antigens to CD8+ T cells. cDC1s also secrete cytokines that allow 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. In this study, we used a multiplexed immunofluorescence analysis pipeline coupled with computational image analysis to determine the spatial organization of cDC1s in skin lesions from a cohort of patients with advanced melanoma treated with immune checkpoint inhibitors (ICI). For this, we performed a whole-slide image analysis of cDC1 infiltration, distribution, and spatial interaction with key immune partners such as CD8+ T cells and plasmacytoid DCs. We also analyzed LAMP3+ DCs, which correspond to a mature subset of tumor-infiltrating DCs. Distance and cell network analyses demonstrated that cDC1s exhibited a scattered distribution compared with tumor-infiltrating plasmacytoid DCs and LAMP3+ DCs, which were preferentially organized in dense areas with high homotypic connections. The proximity and interactions between CD8+ T cells and cDC1s were positively associated with the response to ICIs. In conclusion, our study unravels the complex spatial organization of cDC1s and their interactions with CD8+ T cells in lesions of patients with melanoma, shedding light on the pivotal role of these cells in shaping the response to ICIs.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"517-526"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","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":"Lung Cancer-Intrinsic SOX2 Expression Mediates Resistance to Checkpoint Blockade Therapy by Inducing Treg-Dependent CD8+ T-cell Exclusion.","authors":"Elen Torres-Mejia, Sally Weng, Charlie A Whittaker, Kim B Nguyen, Ellen Duong, Leon Yim, Stefani Spranger","doi":"10.1158/2326-6066.CIR-24-0184","DOIUrl":"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. In this study, 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 (Treg). CD8+ T-cell exclusion depended on Treg-mediated suppression of tumor vasculature. Depleting tumor-infiltrating Tregs via glucocorticoid-induced TNF receptor-related protein 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 patients with non-small cell lung cancer with SOX2-dependent CD8+ T-cell exclusion would benefit from the depletion of glucocorticoid-induced TNFR-related protein-positive Tregs.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"496-516"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964848/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKCδ Germline Variants and Genetic Deletion in Mice Augment Antitumor Immunity through Regulation of Myeloid Cells.","authors":"Kyle R Cron, Ayelet Sivan, Keston Aquino-Michaels, Andrea Ziblat, Emily F Higgs, Randy F Sweis, Ruxandra Tonea, Seoho Lee, Thomas F Gajewski","doi":"10.1158/2326-6066.CIR-23-0999","DOIUrl":"10.1158/2326-6066.CIR-23-0999","url":null,"abstract":"<p><p>Based on the notion that hypomorphic germline genetic variants are linked to autoimmune diseases, we reasoned that novel targets for cancer immunotherapy might be identified through germline variants associated with greater T-cell infiltration into tumors. Here, we report that while investigating germline polymorphisms associated with a tumor immune gene signature, we identified protein kinase C delta (PKCδ) as a candidate. Genetic deletion of Prkcd in mice resulted in improved endogenous antitumor immunity and increased efficacy of anti-PD-L1. Single-cell RNA sequencing revealed myeloid cell expression of Prkcd, and PKCδ deletion caused a shift in macrophage gene expression from an M2-like to an M1-like phenotype. Conditional deletion of Prkcd in myeloid cells recapitulated improved tumor control that was augmented further with anti-PD-L1. Analysis of clinical samples confirmed an association between PRKCD variants and M1/M2 phenotype, as well as between a PKCδ knockout-like gene signature and clinical benefit from anti-PD-1. Our results identify PKCδ as a candidate therapeutic target that modulates myeloid cell states.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"547-559"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977624","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}