Cancer immunology research最新文献

{"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}

{"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":"The Bidirectional Interplay between T Cell-Based Immunotherapies and the Tumor Microenvironment.","authors":"Alfredo Pherez-Farah, Gioia Boncompagni, Aleksey Chudnovskiy, Giulia Pasqual","doi":"10.1158/2326-6066.CIR-24-0857","DOIUrl":"10.1158/2326-6066.CIR-24-0857","url":null,"abstract":"<p><p>T cell-based therapies, including tumor-infiltrating lymphocyte therapy, T-cell receptor-engineered T cells, and chimeric antigen receptor T cells, are powerful therapeutic approaches for cancer treatment. Whereas these therapies are primarily known for their direct cytotoxic effects on cancer cells, accumulating evidence indicates that they also influence the tumor microenvironment (TME) by altering the cytokine milieu and recruiting additional effector populations to help orchestrate the antitumor immune response. Conversely, the TME itself can modulate the behavior of these therapies within the host by either supporting or inhibiting their activity. In this review, we provide an overview of clinical and preclinical data on the bidirectional influences between T-cell therapies and the TME. Unraveling the interactions between T cell-based therapies and the TME is critical for a better understanding of their mechanisms of action, resistance, and toxicity, with the goal of optimizing efficacy and safety.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"463-475"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945094","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":"The Problem with Syngeneic Mouse Tumor Models.","authors":"Nils Lonberg","doi":"10.1158/2326-6066.CIR-24-1046","DOIUrl":"10.1158/2326-6066.CIR-24-1046","url":null,"abstract":"<p><p>The advent of syngeneic mouse tumor models provided the scientific foundation for cancer immunotherapies now in widespread use. However, in many respects, these models do not faithfully recapitulate the interactions between cancer cells and the immune systems of human patients who have solid tumors because they represent a very early stage in the immune response to the newly transplanted cancer cells compared with the relatively mature stage found in human patients at the time of treatment. The lack of translatability of syngeneic models is probably responsible for many failed clinical trials conducted at considerable expense, involving far too many patients with cancer who received no benefit. Better mouse models would substantially accelerate the pace of discovery of new immunotherapies. Until these models emerge, a better understanding of the differences between the existing syngeneic models and human cancers may provide a more efficient path for moving experimental drugs into clinical development. To accomplish this, we must consider mice transplanted with syngeneic tumor cells to be in vivo assays, potentially useful for understanding the mechanism of action of immunotherapies rather than disease models.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"456-462"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490862","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":"Host Tissue Factors Predict Immune Surveillance and Therapeutic Outcomes in Gastric Cancer.","authors":"Miseker Abate, Emily E Stroobant, Teng Fei, Ya-Hui Lin, Shoji Shimada, Harrison Drebin, Eunise Chen, Laura H Tang, Sohrab P Shah, Jedd D Wolchok, Yelena Y Janjigian, Vivian E Strong, Santosha A Vardhana","doi":"10.1158/2326-6066.CIR-23-0563","DOIUrl":"10.1158/2326-6066.CIR-23-0563","url":null,"abstract":"<p><p>The immune composition of solid tumors is typically inferred from biomarkers, such as histologic and molecular classifications, somatic mutational burden, and PD-L1 expression. However, the extent to which these biomarkers predict the immune landscape in gastric adenocarcinoma-an aggressive cancer often linked to chronic inflammation-remains poorly understood. We leveraged high-dimensional spectral cytometry to generate a comprehensive single-cell immune landscape of tumors, normal tissue, and lymph nodes from patients in the Western Hemisphere with gastric adenocarcinoma. The immune composition of gastric tumors could not be predicted by traditional metrics such as tumor histology, molecular classification, mutational burden, or PD-L1 expression via IHC. Instead, our findings revealed that innate immune surveillance within tumors could be anticipated by the immune profile of the normal gastric mucosa. Additionally, distinct T-cell states in the lymph nodes were linked to the accumulation of activated and memory-like CD8+ tumor-infiltrating lymphocytes. Unbiased reclassification of patients based on tumor-specific immune infiltrate generated four distinct subtypes with varying immune compositions. Tumors with a T cell-dominant immune subtype, which spanned The Cancer Genome Atlas molecular subtypes, were exclusively associated with superior responses to immunotherapy. Parallel analysis of metastatic gastric cancer patients treated with immune checkpoint blockade showed that patients who responded to immunotherapy had a pretreatment tumor composition that corresponded to a T cell-dominant immune subtype from our analysis. Taken together, this work identifies key host-specific factors associated with intratumoral immune composition in gastric cancer and offers an immunological classification system that can effectively identify patients likely to benefit from immune-based therapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"591-601"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945090","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":"PRDM1 Is a Key Regulator of the NKT-cell Central Memory Program and Effector Function.","authors":"Gengwen Tian, Gabriel A Barragan, Hangjin Yu, Claudia Martinez-Amador, Akshaya Adaikkalavan, Xavier Rios, Linjie Guo, Janice M Drabek, Osmay Pardias, Xin Xu, Antonino Montalbano, Chunchao Zhang, Yanchuan Li, Amy N Courtney, Erica J Di Pierro, Leonid S Metelitsa","doi":"10.1158/2326-6066.CIR-24-0259","DOIUrl":"10.1158/2326-6066.CIR-24-0259","url":null,"abstract":"<p><p>Natural killer T cells (NKTs) are a promising platform for cancer immunotherapy, but few genes involved in the regulation of NKT therapeutic activity have been identified. To find regulators of NKT functional fitness, we developed a CRISPR/Cas9-based mutagenesis screen that uses a guide RNA (gRNA) library targeting 1,118 immune-related genes. Unmodified NKTs and NKTs expressing a GD2-specific chimeric antigen receptor (GD2.CAR) were transduced with the gRNA library and exposed to CD1d+ leukemia or CD1d-GD2+ neuroblastoma cells, respectively, over six challenge cycles in vitro. Quantification of gRNA abundance revealed enrichment of PRDM1-specific gRNAs in both NKTs and GD2.CAR NKTs, a result that was validated through targeted PRDM1 knockout. Transcriptional, phenotypic, and functional analyses demonstrated that CAR NKTs with PRDM1 knockout underwent central memory-like differentiation and resisted exhaustion. However, these cells downregulated the cytotoxic mediator granzyme B and showed reduced in vitro cytotoxicity and only moderate in vivo antitumor activity in a xenogeneic neuroblastoma model. In contrast, short hairpin RNA-mediated PRDM1 knockdown preserved effector function while promoting central memory differentiation, resulting in GD2.CAR NKTs with potent in vivo antitumor activity. Thus, we have identified PRDM1 as a regulator of NKT memory differentiation and effector function that can be exploited to improve the efficacy of NKT-based cancer immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"577-590"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000907","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":"CD103+CD56+ ILCs Are Associated with an Altered CD8+ T-cell Profile within the Tumor Microenvironment.","authors":"Douglas C Chung, Noor Shakfa, Jehan Vakharia, Kathrin Warner, Nicolas Jacquelot, Azin Sayad, SeongJun Han, Maryam Ghaedi, Carlos R Garcia-Batres, Jules Sotty, Arvin Azarmina, Ferris Nowlan, Edward L Y Chen, Michael Zon, Alisha R Elford, Ben X Wang, Linh T Nguyen, Miralem Mrkonjic, Blaise A Clarke, Marcus Q Bernardini, Benjamin Haibe-Kains, Sarah E Ferguson, Sarah Q Crome, Hartland W Jackson, Pamela S Ohashi","doi":"10.1158/2326-6066.CIR-24-0151","DOIUrl":"10.1158/2326-6066.CIR-24-0151","url":null,"abstract":"<p><p>Immunotherapies have had unprecedented success in the treatment of multiple cancer types, albeit with variable response rates. Unraveling the complex network of immune cells within the tumor microenvironment (TME) may provide additional insights to enhance antitumor immunity and improve clinical response. Many studies have shown that NK cells or innate lymphoid cells (ILC) have regulatory capacity. Here, we identified CD103 as a marker that was found on CD56+ cells that were associated with a poor proliferative capacity of tumor-infiltrating lymphocytes in culture. We further demonstrated that CD103+CD56+ ILCs isolated directly from tumors represented a distinct ILC population that expressed unique surface markers (such as CD49a and CD101), transcription factor networks, and transcriptomic profiles compared with CD103-CD56+ NK cells. Using single-cell multiomic and spatial approaches, we found that these CD103+CD56+ ILCs were associated with CD8+ T cells with reduced expression of granzyme B. Thus, this study identifies a population of CD103+CD56+ ILCs with potentially inhibitory functions that are associated with a TME that includes CD8+ T cells with poor antitumor activity. Further studies focusing on these cells may provide additional insights into the biology of an inhibitory TME.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"527-546"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623803","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":"Different PD-L1 Assays Reveal Distinct Immunobiology and Clinical Outcomes in Urothelial Cancer.","authors":"Matthew D Galsky, Mark Kockx, Juliette Roels, Roos Van Elzen, Xiangnan Guan, Kobe Yuen, Deepali Rishipathak, Jonathan F Anker, Sacha Gnjatic, Sudeh Izadmehr, Shomyseh Sanjabi, Robert J Johnston, Maureen Peterson, Hartmut Koeppen, Justin M David, Saurabh Gupta, Aristotelis Bamias, Jose Angel Arranz, Eiji Kikuchi, Maria De Santis, Ian D Davis, Patrick Williams, Sandrine Bernhard, Ira Mellman, Enrique Grande, Romain Banchereau, Sanjeev Mariathasan","doi":"10.1158/2326-6066.CIR-24-0649","DOIUrl":"10.1158/2326-6066.CIR-24-0649","url":null,"abstract":"<p><p>Testing for PD-L1 expression by IHC is used to predict immune checkpoint blockade (ICB) benefits but has performed inconsistently in urothelial cancer clinical trials. Different approaches are used for PD-L1 IHC. We analyzed paired PD-L1 IHC data on urothelial cancer samples using the SP142 and 22C3 assays from the phase III IMvigor130 trial and found discordant findings summarized by four phenotypes: PD-L1 positive by both assays, PD-L1 positive by the SP142 assay only, PD-L1 positive by the 22C3 assay only, and PD-L1 negative by both assays double negative. PD-L1 positive by both assays and PD-L1 positive by the SP142 assay only urothelial cancers were associated with more favorable ICB outcomes and increased dendritic cell (DC) infiltration. SP142 PD-L1 staining co-localized with DC-LAMP, a DC marker, whereas 22C3 staining was more diffuse. PD-L1 positive by the 22C3 assay only urothelial cancers, associated with worse outcomes, were enriched in tumor cell (TC)-dominant PD-L1 expression. Multiplex IHC in an independent ICB-treated cohort confirmed that TC-dominant PD-L1 expression was associated with shorter survival. Using different PD-L1 assays, we uncovered that SP142 may preferentially stain PD-L1-expressing DCs, key to orchestrating antitumor immunity, whereas TC-dominant PD-L1 expression, which underlies a subset of \"PD-L1-positive\" specimens, is associated with poor ICB outcomes. See related Spotlight by Karunamurthy and Davar, p. 454 .</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"476-486"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032314","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":"In Situ Detection of Individual Classic MHC-I Gene Products in Cancer.","authors":"Paula I Gonzalez-Ericsson, Susan R Opalenik, Violeta Sanchez, Amy M Palubinsky, Ann Hanna, Xiaopeng Sun, Andres A Ocampo, Guadalupe Garcia, Leonel Maldonado, Zaida Morante, Tatiana Vidaurre, Guillermo Valencia, Henry L Gomez, Melinda E Sanders, Laura C Kennedy, Elizabeth J Phillips, Justin M Balko","doi":"10.1158/2326-6066.CIR-24-1003","DOIUrl":"10.1158/2326-6066.CIR-24-1003","url":null,"abstract":"<p><p>Tumor-specific HLA class I expression is required for cytotoxic T-cell elimination of cancer cells expressing tumor-associated antigens or neoantigens. Cancers downregulate antigen presentation to avoid adaptive immunity. The highly polymorphic nature of the genes encoding these proteins, coupled with quaternary-structure changes after formalin fixation, complicates detection by IHC. In this study, we determined recognition of 16 specific HLA-A, -B, and -C alleles by 15 antibodies commercially available for IHC use, identifying and validating pan and specific HLA-A, -B, and -C antibodies, providing a validated method that can be applied to investigate HLA-A, -B, and -C molecule-specific loss in cancer. We applied this approach to a series of breast cancers as a proof of utility, identifying differential HLA-A, -B, and -C loss, with a higher incidence of HLA-A and -B loss in hormone-driven breast cancers, HLA-B loss in HER2+ cancers, and an equal loss of all three molecules in triple-negative disease. Additionally, we found that at the protein level, HLA-A and -B loss were early events prevalent in premalignant lesions, whereas HLA-C loss was less common throughout tumor evolution. Effective response to immunotherapies such as checkpoint inhibitors and MHC-I-targeted cancer vaccines, which hinge on the carriage of specific allele groups, requires MHC-I expression on tumor cells. These findings have implications for the success of checkpoint inhibitors and vaccine strategies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"602-609"},"PeriodicalIF":8.1,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969016","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}