Cancer immunology research最新文献

{"title":"ULK1-dependent autophagy initiation promotes MHC-I degradation and immune evasion in HPV-positive head and neck cancer.","authors":"Lexi Vu, Nicholas S Giacobbi, Mohamed I Khalil, Canchai Yang, William J Eckerman, Evelyn D Gomez Recinos, Johnathon D Garber, Abigail Z Bennett, Bryttan Adams, Hyomin Son, Prerna Chahal, Dara M Villa, Tanisha Srivastava, Katie R Martin, Craig C Welbon, Caitlin S Williamson, William C Spanos, Jeffrey P MacKeigan, Andrew J Olive, Dohun Pyeon","doi":"10.1158/2326-6066.CIR-26-0421","DOIUrl":"10.1158/2326-6066.CIR-26-0421","url":null,"abstract":"<p><p>Antigen presentation by major histocompatibility complex class I (MHC-I) is critical for tumor cell killing by CD8+ T cells. In human papillomavirus-positive head and neck cancer (HPV+ HNC), where MHC-I downregulation is frequent despite favorable immune cell infiltration, lower MHC-I levels are associated with poor responses to immune checkpoint inhibitor therapy. However, the mechanism of MHC-I degradation remains elusive. Genome-wide CRISPR screens in HPV+ HNC identified components of the ULK1 and PIK3C3 autophagy initiation complexes among top negative regulators of cell-surface MHC-I. In contrast, inhibiting post-initiation stages of autophagy did not restore cell-surface MHC-I, highlighting a critical role for autophagy initiation in regulation of MHC-I. Mechanistically, we showed that MHC-I is recruited from the ER to autophagosomes by the cargo receptor NDP52. Finally, inhibition of autophagy initiation suppressed HPV+ HNC tumor growth in vivo and enhanced the CD8+ T cell-mediated antitumor response. Our findings suggest that autophagic degradation of MARCHF8-ubiquitinated MHC-I is a key immune evasion mechanism in HPV+ HNC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13676309/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073575","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":"Immunophenotyping of CD8+ T Cells in Classical Hodgkin Lymphoma Reveals a Shift Toward Intermediate Exhaustion Following PD-1 Blockade.","authors":"Matthew Salaciak, Tho-Alfakar Al-Aubodah, Samantha J Worme, Laura Widawski, Claudia L Kleinman, Jiannis Ragoussis, Ryan N Rys, Madelyn J Abraham, Angelo Rizzolo, Paige McCallum, Christophe Gonçalves, Gerben Duns, Christian Steidl, Sonia V Del Rincon, Koren K Mann, Ciriaco A Piccirillo, Francois Mercier, Nathalie A Johnson","doi":"10.1158/2326-6066.CIR-26-0127","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0127","url":null,"abstract":"<p><p>The immune microenvironment of classical Hodgkin lymphoma (cHL) is characterized by rare Hodgkin-Reed-Sternberg (HRS) cells surrounded by dysfunctional lymphocytes. HRS cells exploit the PD-L1/PD-1 axis to suppress antitumor immunity. Although PD1 blockade is effective in some relapsed cHL patients, the mechanisms of resistance remain unclear. We investigated T-cell dynamics in cHL using whole-exome sequencing (WES) of plasma circulating tumor DNA and longitudinal single-cell RNA and T-cell receptor sequencing of peripheral blood lymphocytes from a relapsed patient before and after anti-PD1 therapy. Findings were validated by flow cytometry in 11 relapsed cHL patients (pre- and post anti-PD1) and 6 healthy age-matched controls, and by PhenoCycler imaging of 18 tissue biopsies (13 diagnostic, 5 post anti-PD1). WES identified two somatic mutations at relapse-MEX3B-Lys201* and TNFRSF10A-Tyr409His-potentially contributing to immune escape. Immune profiling revealed clonal expansion of CD8⁺ T cells at relapse and a shift from precursor-like (TCF1⁺) to intermediately exhausted (CX3CR1⁺) phenotypes. This pattern was confirmed in other relapsed cHL patients, in whom TCF1⁺ populations diminished, and CX3CR1⁺ T-bet⁺ populations became dominant among those progressing on anti-PD1 therapy. In post anti-PD1 treatment tissue biopsies, CD8⁺ T cells exhibited increased levels of exhaustion markers (TCF1⁻, CX3CR1⁺), a phenotype not observed in diagnostic cHL or healthy donors. These results suggest that durable anti-PD1 responses depend on the preservation of progenitor-exhausted T cells, whereas relapse post anti-PD1 is marked by the accumulation of intermediately exhausted clones. Strategies to prevent T-cell exhaustion or combine anti-PD1 with approaches targeting antigen burden may help overcome resistance.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073561","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":"IFNγ-dependent tumor-cell MHC-II is restrained by MAPK signaling and associated with immunotherapy responsiveness in pancreatic ductal adenocarcinoma.","authors":"Canping Chen, Yi Zhang, Xi Li, Tugba Y Ozmen, Furkan Ozmen, Shamilene Sivagnanam, Kyle P Gribbin, Katie E Blise, Xinxing Yang, Gangmin Kim, Roselyn S Dai, Dove Keith, Mara H Sherman, Mu-Shui Dai, Lisa M Coussens, Charles D Lopez, Rosalie C Sears, Gordon B Mills, Katelyn T Byrne, Zheng Xia","doi":"10.1158/2326-6066.CIR-25-1612","DOIUrl":"10.1158/2326-6066.CIR-25-1612","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive tumor microenvironment (TME) and poor prognosis. Although major histocompatibility complex class II (MHC-II) is typically expressed by professional antigen-presenting cells, its regulation and significance in malignant PDAC cells remain unclear. Here, we integrated single-cell RNA sequencing, spatial transcriptomics, bulk transcriptomics, multiplex immunohistochemistry, and functional studies in murine PDAC models to investigate tumor-cell MHC-II. Across human PDAC datasets, elevated tumor-cell MHC-II expression was associated with increased CD4⁺ and CD8⁺ T-cell infiltration and localization within immune-rich tumor niches. In paired biopsies from patients treated with cobimetinib, malignant cells showed increased expression of MHC-II pathway genes, suggesting therapy-induced activation of this program. In preclinical KPC models, MHC-IIhigh tumors exhibited greater T-cell infiltration, whereas MHC-IIlow tumors derived the greatest benefit from cobimetinib combined with immune checkpoint blockade. Mechanistically, direct tumor stimulation via in vitro administration of cobimetinib and recombinant interferon (IFN)-γ resulted in MHC-II induction in vitro by both MHCIIhigh and MHC-IIlow PDAC cell lines. In vivo, combined MEK inhibition and immune checkpoint blockade-controlled tumor growth, including in MHC-IIlow tumors. Deletion of the IFN-γ receptor abolished MHC-II induction and therapeutic benefit, demonstrating that this response is IFN-γ dependent. MEK inhibition enhanced downstream IFN-γ signaling and the combination was required for MHC II upregulation in vitro, indicating that MAPK activity restrains an IFN-γ-responsive MHC-II program. Collectively, these findings identify tumor-cell MHC-II as an IFN-γ-dependent, MAPK-restrained program that denotes immunotherapy sensitivity in PDAC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036495","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":"Inducible IL-12 or IL-18 secreting CAR T cells targeting the glyco-antigen CD176 exhibit potent activity against non-small cell lung cancer in preclinical models.","authors":"Chiara Malinconico, Justus Weber, Antonina Jana Polzien, Agnes Bonifacius, Melina Umland, Quentin Deveuve, Tonia Bargmann, Katharina Zimmermann, Johanna Gellert, Lavinia Neubert, Stefan Dübel, Axel Schambach, Armin Braun, Rainer Blasczyk, Hinrich Abken, Michael Hudecek, Anna Christina Dragon, Britta Eiz-Vesper","doi":"10.1158/2326-6066.CIR-25-1399","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1399","url":null,"abstract":"<p><p>To date, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide, underscoring the urgent need for new treatment options. The oncofetal carbohydrate CD176 is masked on healthy tissues but is present on a variety of cancer entities and is associated with cancer invasiveness and metastasis. In this study, we employed chimeric antigen receptor T cells (CAR-Ts) directed against CD176 for treatment of NSCLC. CD176-CAR-Ts were optimized with an additional inducible cassette encoding IL-18 (CD176-iIL18-TRUCKs) or IL-12 (CD176-iIL12-TRUCKs) to augment antitumor reactivity through autocrine and paracrine signaling. CD176-iIL18- and CD176-iIL12-TRUCKs eradicate NSCLC cells in a 3D tumor spheroid model and tissue slices derived from lung adenocarcinoma patients more potently than CD176-CAR-Ts. Administration of TRUCKs in a lung carcinoma xenograft mouse model results in partial or complete tumor eradication in all mice treated with CD176-iIL12-TRUCKs and in 50% of mice treated with CD176-iIL18-TRUCKs. This study highlights the potential of CD176 as a CAR-T-cell target and suggest CD176-CAR-Ts armored with IL-18 or IL-12 as promising new therapeutic approach for the treatment of NSCLC and several other CD176-positive cancer entities.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015656","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":"IL-21 boosts T cell-therapy efficacy for solid tumors by enhancing mitochondrial Ca2+-mediated motility of effector CD8+ T cells.","authors":"Maureen Hoen Rauhut, Fahiima Abdullahi, Jay Walters, Hiten N Patel, Dominik Stich, Isabelle J Marié, Haitao Wen, David E Levy, Jeffrey G Jacot, Jordan Jacobelli, Felipe Valenca-Pereira, Mercedes Rincon","doi":"10.1158/2326-6066.CIR-26-0401","DOIUrl":"10.1158/2326-6066.CIR-26-0401","url":null,"abstract":"<p><p>Cell motility, characterized by random walk and exploratory search movement, enables effector CD8+ T cells to search for sparse antigen-specific cancer targets within a tumor. This is of special relevance for treatment of solid cancers with adoptive T-cell receptor (TCR) T-cell therapy, where administered effector CD8+ T cells recognize specific MHC-I-presented antigens. Cell motility requires cytoskeleton remodeling to facilitate shape changes and movement. Herein, we show that increased mitochondrial Ca2+ levels are essential to reduce cytoskeleton stiffness of effector CD8+ T cells, leading to acquisition of a polarized shape and high motility. IL-21, but not IL-7 or IL-15, was able to raise mitochondrial Ca2+ levels in effector CD8+ T cells and increase their motility without affecting survival and proliferation. This increase in mitochondrial Ca2+ levels triggered by IL-21 was driven by sustaining mitochondrial membrane potential through mitochondrial STAT3, independently of its transcriptional activity. Enhanced motility of effector CD8+ T cells led to a superior killing efficacy of antigen-specific melanoma cells in vitro. Furthermore, enhanced mitochondrial Ca2+-mediated motility of adoptive TCR-specific effector CD8+ T cells resulted in a superior antitumor efficacy of this treatment against solid tumors in vivo. Thus, enhancing effector CD8+ T-cell motility is a promising strategy to boost efficacy of adoptive T-cell therapies against solid tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012030","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":"Subtype-Agnostic Biomarkers of Immunotherapy Response in Lung Cancer.","authors":"Elisa Gobbini, Subhamoy Chakraborty, Ioannis Vathiotis, Roberto Borea, Konstantinos N Syrigos, Nicolas Girard, Asrar Alahmadi, Christian Rolfo, Triparna Sen","doi":"10.1158/2326-6066.CIR-26-0295","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0295","url":null,"abstract":"<p><p>Immunotherapy has transformed the lung cancer treatment landscape, establishing a role in nearly all histologic subtypes, including non-small cell and small cell lung cancers. However, only a few biomarkers, including PD-L1 tumor proportion score, tumor mutational burden, and microsatellite instability, are currently available, and their predictive value remains inconsistent across different histologies. The biological heterogeneity of lung tumors and the dynamic interplay between systemic therapies and the tumor microenvironment (TME) further complicate biomarker development. At the same time, novel immunotherapeutic strategies, including bispecific antibodies and antibody-drug conjugates, are expanding the spectrum of immune targets beyond conventional checkpoint inhibition, highlighting the need for biomarkers that better reflect the functional state of the TME. In this review, we address the limitations of currently used biomarkers across lung cancer histologies and describe emerging immune-related biomarkers encompassing innate immune infiltration, antigen presentation capacity, cytotoxic T-cell activation, and inflammatory signaling; these have shown promise as histology-independent predictors of response. Robust prospective studies are essential to validate integrated signatures capable of capturing profiles of patients who are most likely to respond to immune checkpoint inhibitors and next-generation treatments.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"OF1-OF13"},"PeriodicalIF":7.9,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015663","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":"Histone H3K18 Lactylation Drives Immunosuppression by Upregulating CD38 in Myeloid-Derived Suppressor Cells in Lung Cancer.","authors":"Yao Dai, Haiyan Dai, Yahui Wang, Wenxin Da, Yan Zhang, Wei Zhu, Deqiang Wang, Shengjun Wang, Jie Ma","doi":"10.1158/2326-6066.CIR-25-1401","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1401","url":null,"abstract":"<p><p>Histone lactylation is an epigenetic modification that connects lactate metabolism with protein function. Our study identified lactate enhances the protein lactylation level not only in Myeloid-derived suppressor cells (MDSCs) of tumor-bearing mice, but also in the tumor tissues of lung cancer patients. This modification led to upregulation of CD38 expression and enhanced the immunosuppressive function of MDSCs. Mechanistically, CD38 promoted immunosuppression by depleting NAD⁺, and treatment with CD38 inhibitor or siRNA-mediated knockdown of CD38 in MDSCs delayed tumor progression. H3K18la is enriched at CD38 promoter region, with p300, HDAC1-3, and BRD4 identified as key epigenetic regulators in this process. Our findings reveal the critical role of the lactate-CD38-NAD⁺ axis in regulating MDSC immunosuppressive function and establish histone lactylation as an epigenetic mechanism controlling CD38 expression.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988136","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":"Pre-existing immunity and hrHPV status determine immunotherapy response in advanced penile cancer: biomarkers and overall survival in the PERICLES trial.","authors":"Tynisha S Rafael, Alberto Gil-Jimenez, Laura Elst, Hielke M de Vries, Iris M Seignette, Elise Bekers, Marta Lopez-Yurda, Dennis Peters, Marja Nieuwland, Erik Hooijberg, Annegien Broeks, Oscar R Brouwer, Eva E Schaake, Diether Lambrechts, Lodewyk F A Wessels, Daniel J Vis, Maarten Albersen, Tanja D de Gruijl, Michiel S van der Heijden","doi":"10.1158/2326-6066.CIR-26-0236","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0236","url":null,"abstract":"<p><p>Penile squamous cell carcinoma (PeSCC) is a rare malignancy with limited treatment options in advanced stages. The phase II PERICLES trial (NCT03686332) investigated atezolizumab with or without radiotherapy in advanced penile cancer. Here, we report mature overall survival (OS) and updated progression-free survival (PFS) outcomes and an in-depth biomarker analysis. Patients were treated with atezolizumab monotherapy (n=12) or atezolizumab in combination with radiotherapy (n=20, 33 fractions of 1.5-1.8 Gy) for locoregional disease control. Comprehensive analysis of baseline tumor tissue (n=28/31) was performed using bulk RNA sequencing, immunohistochemistry and multiplex immunofluorescence. Additionally, spatial transcriptomics (n=9) was conducted to further explore functionality and (co-)localization of immune cell subsets. With extended follow-up (median: 38 months), landmark 2-year OS and PFS in the full study cohort was 18.8% (95% CI, 9.1-38.6) and 12.5% (95% CI, 5.0-31.3), respectively. High-risk human papillomavirus (hrHPV)-positive tumors were enriched for IFN-γ and IFN-α signatures, potentially explaining the improved PFS and OS observed in this subgroup. Both stromal CD68+ myeloid cell density and intratumoral CD8+PD1+ T-cell density were associated with non-progression at 1 year. Increased intratumoral CD8+PD1+ T-cell density was also associated with improved PFS and OS, with consistent findings in the hrHPV-positive subgroup. Spatial transcriptomics identified these CD8+ T cells as tissue-resident cytotoxic effector cells co-expressing checkpoint molecules (LAG3 and TIGIT), chemokines (CCL4 and CXCL13), and cytotoxic molecules (PRF1 and GZMB). Interrogation of the penile cancer immune microenvironment highlights CD8+PD1+ T-cells as candidate biomarkers in relation to clinical benefit from immune checkpoint blockade in advanced PeSCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988063","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":"FasL-mediated death of activated intratumoral T cells drives secondary resistance to cancer immunotherapy.","authors":"Chen Qing, Ehsan Ghorani, Kane A Foster, Imran Uddin, Gordon Beattie, Cristobal Costoya, Felipe Galvez-Cancino, Henning Walczak, Maria Amann, Karl S Peggs, Sergio A Quezada","doi":"10.1158/2326-6066.CIR-25-1567","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1567","url":null,"abstract":"<p><p>Cancer progression following an initial response to immunotherapy (secondary resistance; 2°R) is a major and poorly understood problem. We treated mice bearing B16 melanoma with a combination of a regulatory T cell (Treg) depleting, non-IL-2 blocking antibody (anti-CD25NIB) and an autologous cancer cell vaccine (GVAX). The regimen yielded initial tumor shrinkage followed by 2°R; lethal progression occurred in ~90% of partially responsive (PR) tumors by days 35-50. Cell lines derived from 2°R tumors retained treatment sensitivity upon re-implantation into naïve mice, suggesting resistance was related to a loss of immune control over time. Profiling PR and 2°R tumors by flow cytometry and single-cell RNA/TCR sequencing, we found that activated CD8⁺ T cells with tumor-reactive features declined in abundance, whereas non-activated T cells and Tregs increased. Activated CD8⁺ cells showed heightened TCR stimulation, clonal expansion, and expression of apoptotic signatures and death receptors, including Fas. Their loss was not explained by lymph node accumulation or differentiation to non-activated states. These findings were validated in a clinically relevant MC38 colon carcinoma model treated with anti-PD-L1 checkpoint blockade, confirming that depletion of activated, tumor-reactive clones is a shared mechanism of 2°R across therapeutic modalities. Fas ligand (FasL) blockade reversed this loss and prolonged survival. Longitudinal transcriptional and tissue staining data from human checkpoint blockade studies similarly indicated that activated T cells decline in abundance over time and at 2°R. These findings implicate death of activated T cells as a mechanism of 2°R and suggest Fas-FasL blockade may extend response durability.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976004","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":"Phenotypic and functional characterization of tumor-reactive T cells in malignant pleural effusions.","authors":"Noam S Gaiger, Jack Coburn, Mark N Lee, Lin Zhang, Heng-Le Chen, Gavitt A Woodard, Harriet M Kluger, David A Schoenfeld, Benjamin Y Lu","doi":"10.1158/2326-6066.CIR-26-0293","DOIUrl":"10.1158/2326-6066.CIR-26-0293","url":null,"abstract":"<p><p>Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) is effective for treating advanced melanoma but requires surgical tumor resection. Malignant pleural effusions (MPE) may provide a more accessible source of tumor-reactive T cells. Synchronously collected MPE, lung metastasis, and blood from a patient with metastatic melanoma were analyzed using high-dimensional flow cytometry, and single-cell RNA/T cell receptor (TCR) sequencing. TCR reactivity to autologous tumor was tested in vitro. The proliferative and cytotoxic capacity of ex vivo expanded T cells was assessed in vitro. MPE contained a higher fraction of CD3+ T cells compared with tumor and was enriched for effector CD8+ T cells and effector memory CD4+ T cells. Compared with TIL, MPE T cells exhibited lower features of T cell exhaustion and higher cytotoxicity signatures. The clonal repertoire of MPE and tumor highly overlapped, including 62.2% of predicted neoantigen-specific (NeoTCR) clonotypes. MHC class I-restricted reactivity was functionally confirmed in two of four selected NeoTCR clonotypes. MPE T cells demonstrated higher proliferative capacity under high-dose IL-2 expansion relative to TIL and achieved comparable MHC class I-dependent tumor killing. Overall, MPE contains polyclonal, tumor-reactive T cells with favorable functional features, supporting MPE as an accessible source for TIL therapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944358","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}