Cancer immunology research最新文献

{"title":"Malignant Ascites Harbors Immune Niche with IL-10 Enriched Effector Dysfunction and Persistent Cancer-Binding IgG.","authors":"Elana R Shaw, Alexei G Hernandez, Linda Huang, Bryan C Szeglin, Yuqian Wang, Carolyn M Merwanji, Rosela Golloshi, Matthew Dunworth, Shannon N Radomski, Charles Lim, David Lichtman, Patrick Balao, John Texter, John Woller, Christopher J VandenBussche, Patrizio Caturegli, LuAnn Rezavi, Conlan Tran, Christopher J Thoburn, Joel S Bader, Felipe Andrade, Maximilian F Konig, Won Jin Ho, Andrew J Ewald","doi":"10.1158/2326-6066.CIR-26-0305","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0305","url":null,"abstract":"<p><p>Malignant ascites provides a window into cancer-immune interactions in the peritoneal cavity. Using Cytometry by Time of Flight (CyTOF), we analyzed ascitic immune cells collected from patients with advanced gastrointestinal cancers, nonmalignant forms of hepatitis (NMH), and healthy control peripheral blood mononuclear cells (HC PBMCs). Compositionally, ascitic immune cells shared a myeloid-rich, B and naïve T cell-low signature relative to HC PBMCs. Underneath the shared ascitic compositional signature, three major functional immunophenotypes emerged in response to exogenous stimulation along a suppressive to cytotoxic axis, aligning with Luminex measurements of ascitic cytokine levels: IL-10 enriched, Nonpolarized, and Granzyme B (GZMB) enriched. In our cohort, the IL-10 enriched functional immunophenotype was exclusive to samples from patients with cancer while the GZMB enriched response was dominated by NMH samples. Ascites from patients with pancreatic ductal adenocarcinoma (PDAC) contained a persistent anti-cancer humoral response characterized by IgG that bound to autologous ascitic PDAC cells and multiple allogeneic PDAC cell lines.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223372","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":"Disruption of the CRL5 ubiquitin ligase complex enhances engineered T-cell persistence under chronic tumor antigen exposure.","authors":"Stefanie Bachl, Carter Ching, Alexis Talbot, Antoine Forget, Nupura Kale, Clara Kochendoerfer, William A Nyberg, Zhongmei Li, Peixin Amy Chen, Patrick H Kennedy, Qi Liu, Joseph J Muldoon, Chang Liu, Gwendolyn Cusing, Nadia Arang, Nevan J Krogan, Greg M Allen, Alexander Marson, Stacie E Dodgson, Justin Eyquem, Julia Carnevale","doi":"10.1158/2326-6066.CIR-26-0608","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0608","url":null,"abstract":"<p><p>Engineered T-cell therapies are limited by progressive dysfunction under chronic tumor antigen exposure, and genetic perturbation of negative regulators has emerged as a promising strategy to sustain effector activity. We reanalyzed a genome-wide CRISPR knockout screen in primary human T cells under repetitive tumor stimulation; protein-protein interaction mapping revealed seven members of the Cullin-RING Ligase 5 (CRL5) complex as an enriched hit cluster. Knockout of any of these members (CUL5, ARIH2, RNF7, UBE2F, UBE2L3, CISH, DCUN1D3) enhanced tumor serial killing, and CUL5, the complex scaffold, emerged as the strongest target. CUL5 knockout T cells exhibited sustained cytotoxicity, elevated effector cytokine production, and fewer exhaustion marker-positive cells while retaining antigen specificity and cytokine dependence. Quantitative ubiquitylation proteomics in resting, and acutely and chronically stimulated T cells mapped CRL5-dependent candidate substrates beyond the canonical JAK/STAT axis, including nutrient transporters, receptor trafficking proteins, and TCR signaling components. The benefit of CUL5 knockout extended across CARs targeting CD19, BCMA, and HER2 with different costimulatory domains, and to 1XX-modified CAR and HLA-independent TCR architectures. Combining CUL5 ablation with a tumor-induced IL-2 circuit produced tumor control across nine rounds of repetitive stimulation, whereas either modification alone eventually failed. In vivo, CUL5 knockout BCMA CAR T cells were enriched in the bone marrow following repeated tumor rechallenge and exhibited enhanced ex vivo cytotoxicity after nearly 90 days in tumor-bearing mice. These findings position CUL5 perturbation as a strategy to improve T-cell persistence and the efficacy of adoptive cell therapies, potentially with engineered cytokine support.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191152","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":"Cullin-5 RING E3 ligase limits CD8⁺ T-cell persistence and effector responses during chronic antigen stimulation.","authors":"Justin D Saco, Daniel Karin, J J Patten, Stefanie Bachl, Carter Ching, Nupura Kale, Yichen Fan, Egmidio Medina, Nataly Naser Al Deen, Ameya Champhekar, William G Kaelin, Brenda A Schulman, Katie M Campbell, Julia Carnevale, Cristina Puig-Saus, Antoni Ribas","doi":"10.1158/2326-6066.CIR-26-0181","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0181","url":null,"abstract":"<p><p>T-cell exhaustion limits durable antitumor responses and remains a barrier to adoptive cell therapies (ACT) in solid tumors. To identify regulators of T-cell persistence, we performed genome-wide CRISPR knockout screens in primary human CD8⁺ T cells expressing an NY-ESO-1-specific T-cell receptor and subjected them to repeated tumor cell rechallenge. These screens revealed enrichment of single-guide RNAs targeting components of Cullin-RING E3 ligases, particularly Cullin-5 (CRL5) assemblies comprising CUL5, RNF7, and ARIH2. Disruption of CRL5 genes in T cells preserved cytotoxic activity and enhanced cytokine production while sustaining effector-associated transcriptional programs and suppressing exhaustion-related signatures. Pharmacologic inhibition of cullin neddylation with the NEDD8-activating enzyme inhibitor MLN4924 recapitulated CRL5 loss and enhanced T-cell effector function in vitro. In a human melanoma xenograft model, ACT with CRL5-deficient T cells improved tumor control. Together, these findings identify CRL5 as a negative regulator of T-cell fitness and a potential therapeutic target to enhance ACT durability in solid tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149191162","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 CCR1/CCR2 attenuates cytokine release syndrome while preserving CAR T-cell antitumor activity.","authors":"Yan-Ruide Li, Yuning Chen, Yichen Zhu, Annabel S Zhao, Xinyuan Shen, Thomas Yuen, Shelby Yeh, Danna Marie Padua, Kaixu Zou, Zhaojun Qiu, Jie Huang, Lili Yang","doi":"10.1158/2326-6066.CIR-26-0770","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0770","url":null,"abstract":"<p><p>Cytokine release syndrome (CRS) is a major dose-limiting toxicity of chimeric antigen receptor (CAR) T-cell therapy, yet the upstream mechanisms driving macrophage activation remain incompletely understood. Here, we established a xenograft model of human CAR T-cell therapy that recapitulates key features of CRS and combined single-cell RNA sequencing (scRNA-seq) with pharmacological intervention to define the inflammatory programs underlying CRS. CAR T-cell treatment induced dose-dependent systemic inflammation and remodeled the host myeloid compartment, leading to the accumulation of a distinct population of CRS-associated macrophages. Analysis of clinical scRNA-seq datasets from CAR T cell-treated glioblastoma patients confirmed enrichment of the CRS-associated macrophage gene signature following therapy in patients, supporting the clinical relevance of our findings. Transcriptomic analyses identified marked upregulation of the chemokine receptors CCR1 and CCR2 together with activation of CCL3- and CCL2-associated signaling pathways. Pharmacological inhibition of CCR1 and CCR2 significantly reduced clinical CRS, inflammatory cytokine production, and macrophage activation while preserving CAR T-cell expansion, effector cytokine production, and in vivo antitumor efficacy. These findings identify CCR1/CCR2-dependent chemokine signaling as a critical regulator of macrophage-driven CRS and support chemokine receptor blockade as a promising strategy to improve the safety of CAR T-cell therapy without compromising therapeutic efficacy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178798","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":"Addition of chemotherapy to radiotherapy promotes progenitor-exhausted CD8⁺ T-cell clonal dominance in head and neck cancer.","authors":"Charleen Chan Wah Hak, Anton Patrikeev, Antonio Rullan, Emmanuel C Patin, Victoria Roulstone, Lisa C Hubbard, Matthew Guelbert, Elizabeth S Appleton, Shane Foo, Isaac Dean, Amy Burley, Joan N Kyula-Currie, Holly Baldock, Jen Y Lee, Pablo Nenclares, Hannah Nanapragasam, Carmen Murano, Malin Pedersen, Maggie Chon U Cheang, Shreerang A Bhide, Masahiro Ono, Kevin J Harrington, Alan A Melcher","doi":"10.1158/2326-6066.CIR-26-0706","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0706","url":null,"abstract":"<p><p>Concomitant chemoradiotherapy (CRT) is a standard-of-care treatment for unresectable locally advanced head and neck squamous cell carcinoma (LA-SCCHN), but its immune effects, particularly relative to radiotherapy (RT) alone, remain incompletely understood. Using syngeneic murine models, we integrated Nr4a3-Tocky reporter analysis with single-cell transcriptomics and T cell receptor clonotyping to comprehensively profile intratumoural CD8⁺ T-cell responses following RT and CRT. We show that CRT uniquely drives robust clonal expansion of antigen-engaged CD8⁺ T-cells and biases differentiation toward progenitor-exhausted (TPEX) states, whereas RT favours terminal exhaustion (TEX). Single-cell analyses further reveal preferential clonal dominance within TPEX populations following CRT. In peripheral blood mononuclear cells from patients treated with CRT, TEX populations predominated early after treatment, followed by delayed expansion of circulating TPEX-like populations at 3 months, suggesting phased recovery of progenitor-like T-cell states. Together, these findings demonstrate that CRT and RT induce distinct CD8⁺ T-cell differentiation trajectories and clonal architectures, providing insight into treatment-induced immune remodelling in LA-SCCHN.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163595","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":"TCR sensitivity shapes recognition of tumor antigen presented by host cells and TCR-T cell efficacy in solid tumors.","authors":"Mete Can Odabasi, Thomas Kammertoens, Elfriede Nößner, Kordelia Hummel, Matthias Richter, Anje Sporbert, Manuel Wagner, Wolfgang Uckert, Thomas Blankenstein, Matthias Leisegang","doi":"10.1158/2326-6066.CIR-26-0367","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0367","url":null,"abstract":"<p><p>Despite advances in adoptive T cell therapy, therapeutic efficacy in solid tumors remains inconsistent, and the mechanistic determinants of treatment failure are incompletely understood. Increasing evidence suggests that effective antitumor responses depend not only on direct recognition of malignant cells but also on interactions with the tumor microenvironment, including non-malignant host cells that cross-present tumor antigens. Using an HLA-A2-transgenic syngeneic mouse cancer model that enables near-physiological presentation of human tumor antigens by both malignant and host cells, we investigated how TCR antigen sensitivity relates to therapeutic outcome. We compared T cell receptor-engineered (TCR-)T cells with different antigen sensitivities directed against the same HLA-A2-restricted melanoma antigen. Although high- and low-sensitivity TCR-T cells recognized tumor cells comparably in vitro, only high-sensitivity TCR-T cells mediated durable tumor regression in vivo. Improved tumor control correlated with enhanced recognition of cross-presented tumor antigen on tumor-associated CD11b+ myeloid cells and increased intratumoral effector activity. IFN-γ levels in tumor tissue and peripheral blood reflected intratumoral T cell activity and correlated with therapeutic response. Together, these findings identify host cell antigen recognition as a sensitivity-dependent functional correlate of TCR-T cell efficacy and provide a mechanistic explanation for the superior activity of higher-sensitivity TCRs in solid tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165749","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 Modular CAR: Adapting T Cells without Reengineering Them.","authors":"Melgious Jin Yan Ang, Zhangyi Luo, Michael J Mitchell","doi":"10.1158/2326-6066.CIR-26-0906","DOIUrl":"10.1158/2326-6066.CIR-26-0906","url":null,"abstract":"<p><p>The therapeutic potential of chimeric antigen receptor (CAR) T cells has long been limited by the static nature of the engineered receptor; once manufactured, the cell is committed to a single antigen, unable to respond to the immune evasion and antigen heterogeneity that define solid tumors. Although solutions such as bispecific constructs and logic-gated circuits have been proposed, each encodes additional complexity into the cell product at the time of manufacture, with no capacity for post-infusion reprogramming. In this issue, Kuo and colleagues report a fundamentally different strategy-the meditope-enabled CAR-in which a small, structurally orthogonal peptide-docking interface is embedded into the extracellular domain of the CAR, converting a fixed cellular product into a programmable platform that can be redirected, selectively expanded, or precisely tracked by administering a modular adapter molecule. See related article by Kuo et al., p. 1553.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1536-1537"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891179","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":"Immune Hallmarks of Recurrent Immune Checkpoint Inhibitor-Mediated Inflammatory Arthritis.","authors":"Synat Keam, Yuanteng Jeff Li, Yanshuo Chu, Jean H Tayar, Huifang Lu, Michael Wu, Sandeep K Agarwal, Nitin Jain, Pavlos Msaouel, Adi Diab, Linghua Wang, Cara Haymaker, Roza Nurieva, Sang T Kim","doi":"10.1158/2326-6066.CIR-25-1639","DOIUrl":"10.1158/2326-6066.CIR-25-1639","url":null,"abstract":"<p><p>Immune checkpoint inhibitor (ICI) therapy is often associated with immune-related adverse events including inflammatory arthritis (IA). However, the mechanisms underlying ICI-mediated IA (ICI-IA), especially its recurrence, are not well understood. In this study, we sought to elucidate mechanisms of recurrent ICI-IA by analyzing longitudinal synovial fluid (SF) samples from patients with ICI-IA. SF samples were collected from six patients with ICI-IA at the first and second occurrences of ICI-IA and analyzed with single-cell RNA sequencing (n = 3), single-cell T-cell receptor sequencing (n = 3), single-cell B-cell receptor sequencing (n = 3), and flow cytometry (n = 6). SF samples from cancer-naïve patients with osteoarthritis (n = 6) were used as negative controls. Analysis revealed that effector CD8+ T cells and PD-1hiCXCL13hi CD4+ T cells were enriched in the SF of patients with ICI-IA. A total of 93% and 50% of the top 10 expanded clones of effector CD8+ T cells and PD-1hiCXCL13hi CD4+ T cells, respectively, were shared between the first and second ICI-IA flares. These top clones were characterized by the production of pro-inflammatory type 1 cytokines including IFNγ, TNFα, and IL21, especially in the second flare, suggesting immune memory responses to cognate antigen. Cell-cell communication analysis suggested that effector CD8+ T cells and PD-1hiCXCL13hi CD4+ T cells interacted with each other and with myeloid cells and B cells through chemokines (CXCL9/10/11/13 and CCL3) and cytokines (macrophage inhibitory factor and IL2/7/15/21). Overall, longitudinal SF analysis from patients with ICI-IA revealed the expansion of effector CD8+ T cells and PD-1hiCXCL13hi CD4+ T cells with type 1 cytokine signatures that potentially contribute to the development or recurrence of ICI-IA.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1653-1669"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13557767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629211","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":"A reciprocally masked anti-CD47/IL-2 fusion protein promotes antitumor immunity and limits systemic toxicity.","authors":"Elise Léchine, Laura Cons, Laure Garnier, Pauline Malinge, Valéry Moine, Juan C Osorio, Limin Shang, Nicolas Fischer, Stéphanie Hugues, Christoph Scheiermann, Walter Ferlin","doi":"10.1158/2326-6066.CIR-26-0459","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0459","url":null,"abstract":"<p><p>Cancer immunotherapies have achieved meaningful clinical benefit but remain limited by systemic toxicities that restrict the use of potent immune modulators. CD47-targeting antibodies promote tumor cell phagocytosis but are hindered by hematologic toxicity, while IL-2 activates cytotoxic lymphocytes but induces broad, dose-limiting immune activation. Here, we engineered a reciprocally masked antibody-cytokine fusion (aCD47/IL-2c) designed for tumor-selective activation. In this construct, a CD47-specific antibody (aCD47) and an IL-2/IL-2 receptor complex (IL2c) sterically and functionally suppress each other via protease-cleavable linkers, preventing CD47 blockade and IL-2 receptor engagement in circulation while enabling protease-dependent unmasking within the tumor microenvironment. A human construct demonstrated masking and protease-dependent restoration of both CD47-SIRPα blockade and IL-2 signaling, with improved systemic tolerability in human hCD47/hSIRPα transgenic mice, supporting translational potential. A murine analog enabled mechanistic and efficacy studies in immunocompetent tumor models. The tolerability of mouse aCD47/IL-2c was improved in comparison to individual components. Antitumor activity required both CD47 blockade and IL-2 activity, and resulted in a robust antitumor efficacy, including in an immune checkpoint-resistant melanoma model. The robust antitumor efficacy was associated with inflammatory macrophage polarization and increased numbers of effector CD8⁺ T cells inside the tumor. Unlike conventional CD47 antibodies or IL-2 therapies, this approach enabled coordinated, tumor-localized activation of innate and adaptive immunity while limiting systemic exposure. Together, these data highlight reciprocal masking as a clinically relevant strategy to expand the therapeutic index of immune modulators constrained by systemic toxicity.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104478","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":"CD4+ T Cells Play Distinct Roles during the Priming versus Effector Phases of Immune Checkpoint Therapy-Dependent Tumor Elimination by CD8+ T Cells.","authors":"Samuel Ameh, Derek J Theisen, Mahima Thapa, Jackson S Turner, Abhinav Rangarajan, Christopher A Nelson, Aaron J Schmitz, Yuang Song, Ruan F Vieira Medrano, Cora D Arthur, J Michael White, Kathleen C F Sheehan, Daved H Fremont, Ali H Ellebedy, Hussein Sultan, Robert D Schreiber","doi":"10.1158/2326-6066.CIR-25-1652","DOIUrl":"10.1158/2326-6066.CIR-25-1652","url":null,"abstract":"<p><p>It is well established that CD4+ T cells play a critical role in facilitating immune checkpoint therapy (ICT). Although CD4+ T-cell function in lymph nodes during CD8+ T-cell priming has been well investigated, their requirement at the effector phase in the tumor is only now beginning to be appreciated. Herein, we used our major histocompatibility complex class II-negative (MHC-II-) sarcoma models to confirm that CD4+ T cells are essential not only during T-cell priming but also to maintain T-cell effector function within the tumor. Depleting CD4+ T cells at the effector phase, after CD8+ T-cell priming had occurred, abolished ICT-induced tumor rejection despite the detection of tumor-specific CD8+ T cells and their intratumoral accumulation. CD4+ T cells were required for functional reinvigoration of CD8+ tumor-infiltrating lymphocytes by ICT, leading to enhanced cytokine production, expression of cytotoxicity, and reduced exhaustion-without affecting CD8+ T-cell proliferation. Mechanistically, CD4+ T-cell function at the effector phase did not require CD40/CD40L signaling, which is necessary for efficient priming but rather depended on IL2 and IFNγ. Using a T-cell receptor-mimic monoclonal antibody (1G10) specific for the dominant neoantigen:I-Ab complex on antigen-presenting cells formed during T3 sarcoma challenge, we further showed that ongoing MHC-II neoantigen presentation was necessary to sustain CD4+ T-cell help after priming. These findings reveal temporally distinct requirements for CD4+ T-cell help and establish a need for continuous CD4+/CD8+ T-cell cooperation as a prerequisite for anti-PD-1/anti-CTLA-4 ICT efficacy against MHC-II- tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1604-1619"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469203","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}