Cancer immunology research最新文献

{"title":"Automated Computational Flow Cytometry Correlates Decreasing Neutrophil-to-Lymphocyte Ratio to Improved Survival in NSCLC after Immune Checkpoint Blockade.","authors":"Katrien L A Quintelier, Maaike M Hofman, Mandy van Brakel, Cor H Lamers, Ron H J Mathijssen, Daphne W Dumoulin, Cor van der Leest, Ruth Seurinck, Christianne Groeneveldt, Sarah Bonte, Reno Debets, Sofie Van Gassen, Marcella Willemsen, Joachim G J V Aerts, Yvan Saeys","doi":"10.1158/2326-6066.CIR-25-0662","DOIUrl":"10.1158/2326-6066.CIR-25-0662","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) therapy has transformed non-small cell lung cancer (NSCLC) treatment and improved overall survival (OS). However, not all patients are responsive. Using computational cytometry analysis to identify immune cell subsets and early dynamic changes, we aimed to unravel the mechanisms underlying diverse responses to ICB in NSCLC. Peripheral blood from 34 patients with NSCLC treated with nivolumab monotherapy was collected at three time points (baseline, week 2, and week 4, referred to as TP1, TP2 and TP3, respectively). Six flow cytometry panels provided comprehensive immune cell profiling, and an R pipeline was designed for data analysis. Differences in abundances, ratios, and functional marker expression were explored in relation to survival. Two additional cohorts were collected and processed similarly. The computational pipeline provided reliable results and is generalizable to new patient cohorts. A decrease in the neutrophil-to-lymphocyte ratio (NLR) between TP2 and TP3 correlated with longer OS. Additionally, patients with an increase in CD8+ T cells between TP2 and TP3 had a higher survival probability. Lastly, we identified a CD11c+ eosinophil subset that increased in patients with a longer OS. Overall, the automated computational approach could be used to analyze clinical multicenter cytometry data in an objective and a reproducible way. Moreover, potential dynamic biomarkers to assess prognosis during ICB therapy in NSCLC were identified, including changes in NLR, CD8+ T cells, and CD11c+ eosinophils. This provides a foundation for further research, emphasizing validation of the pipeline and biomarkers in larger, diverse cohorts and independent datasets to assess their robustness and generalizability.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1351-1361"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13434295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833670","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":"Cancer Chemoimmunotherapy: Time Will Tell.","authors":"Sam O Kleeman, Yosef Riazat-Kesh, Richard Carvajal, Melina E Marmarelis, Dirk Schadendorf, Elad Sharon, Megan Othus, Caroline Robert, Ferdinandos Skoulidis, Benjamin Izar, Robert G Maki, Tobias Janowitz","doi":"10.1158/2326-6066.CIR-26-0335","DOIUrl":"10.1158/2326-6066.CIR-26-0335","url":null,"abstract":"<p><p>Endogenous circadian programs coordinate physiology across tissues, including immune cell trafficking and drug metabolism. Previous retrospective studies suggested that the timing of immune checkpoint inhibitor delivery may be a modifiable determinant of survival in patients with cancer, with earlier infusions often associated with improved outcomes. Recently, the prospective randomized phase III LungTIME-C01 trial reported that earlier time-of-day (before 3:00 pm) administration of chemoimmunotherapy nearly doubled progression-free survival in patients with non-small cell lung cancer. In this commentary, we examine the trial's clinical design and execution, including protocol amendments and safety reporting that warrant clarification. We consider the mechanistic interpretation of the results, highlighting that the observed effects may reflect contributions from cytotoxic chronopharmacology, circadian immune regulation, and healthcare delivery factors rather than immunotherapy timing alone. We outline implications for future trial design, including factorial approaches to disentangle the timing of immunotherapy from chemotherapy and the need for multicenter validation before scheduling recommendations are widely adopted.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1212-1215"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13434287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204225","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":"Cancer Cell-Intrinsic SSBP4 Enables Tumor Immune Evasion by Promoting Cholesterol Biosynthesis.","authors":"Peiqi Ou, Ittai Eres, Junjie Zhao, Chia-Jung Han, Jaehak Oh, Aeryon Kim, Jiayi Dong, Hong Zhou, Tracy Yamawaki, Chi-Ming Li, Andrew Rankin, Rajkumar Noubade, Xin Yu","doi":"10.1158/2326-6066.CIR-25-1312","DOIUrl":"10.1158/2326-6066.CIR-25-1312","url":null,"abstract":"<p><p>The immunosuppressive tumor microenvironment (TME) contributes to resistance against checkpoint inhibitors. However, the precise factors that shape the immune contexture of the TME remain elusive. In this study, we report that single-stranded DNA binding protein 4 (SSBP4), a previously uncharacterized protein, suppresses intratumoral T-cell activation by promoting excessive cholesteryl ester production in tumor cells. Overexpression of SSBP4 in tumor cells decreased T-cell infiltration and accelerated tumor growth in murine syngeneic tumor models. Conversely, genetic ablation of SSBP4 in tumor cells enhanced T-cell infiltration and inhibited tumor growth in a CD8+ T cell-dependent manner. Mechanistically, SSBP4 upregulated cholesterol synthesis genes, leading to increased production of cholesterol and cholesteryl esters in tumor cells, which directly suppressed CD8+ T-cell activation and function. Furthermore, SSBP4 abrogation significantly improved the efficacy of anti-PD-1 treatment. Thus, in this study, we have identified SSBP4 as a cancer cell-intrinsic regulator of cholesterol metabolism that contributes to tumor immune evasion. See related Spotlight, p. 1210.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1216-1232"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763195","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":"Low-Strength Type I Interferon Signaling Promotes CAR T-cell Treatment Efficacy.","authors":"Erting Tang, Yifei Hu, Guoshuai Cao, Duy-Thuc Nguyen, Nicholas W Asby, Nada S Aboelella, Hanna A Ruiz, Xiaolei Cai, Wenbo Zhang, Yu Zhao, Lishi Xie, Xiufen Chen, Michael R Bishop, Peter A Riedell, James L LaBelle, Justin P Kline, Jun Huang","doi":"10.1158/2326-6066.CIR-25-0691","DOIUrl":"10.1158/2326-6066.CIR-25-0691","url":null,"abstract":"<p><p>CD19-directed chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment landscape for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). However, up to 60% of patients do not achieve a complete response. To uncover determinants of therapeutic efficacy, we analyzed the infusion products (IPs) of eight r/r DLBCL patients with distinct clinical responses to axicabtagene ciloleucel using single-cell transcriptomics. Compared with patients who exhibited progressive disease, IPs of complete responders demonstrated enriched signatures of type I interferon (IFN-I) signaling. Based on these findings, we developed a strategy to improve CD19-directed CAR T-cell treatment efficacy by incorporating IFN-I as an enhancer during the ex vivo manufacturing process, with IFN-I removal before CAR T-cell infusion to avoid in vivo toxicities. For both CD28- and 4-1BB-costimulated second-generation CARs, we found that low-strength IFN-I signaling enhanced CAR T-cell cytotoxicity and treatment efficacy against B-cell lymphoma and leukemia. Our low-strength IFN-I-enhanced CAR T-cell ex vivo manufacturing approach leverages an existing FDA-approved pharmacologic agent, circumvents in vivo interferon-associated toxicities, and remains fully compatible with current CAR constructs and manufacturing workflows. Together, our results establish IFN-I as a potent and costimulation-independent enhancer of CAR T-cell efficacy and provide a translationally feasible approach to enhance CAR T-cell therapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1292-1306"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13249101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147867039","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":"Reprogramming CAR with Cytokine Signaling Increases the Efficacy of CAR T-cell Therapy in Solid Tumor Treatment and Confers Sustained Immune Memory.","authors":"Rongchen Sun, Shang Liu, Xue Yang, Changshuai Che, Zhijie Zhang, Yunfan Wang, Chengrui Zhang, Youyou Yang, Xin Li, Jie Wang, Heng Zheng, Min Guo, Hongping Yin","doi":"10.1158/2326-6066.CIR-25-1490","DOIUrl":"10.1158/2326-6066.CIR-25-1490","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in hematologic malignancies but remains limited in solid tumors because of the immunosuppressive microenvironment, tumor heterogeneity, poor immune cell infiltration, and progressive T-cell dysfunction. Because cytokine costimulation is critical for maintaining T-cell fitness, we developed a modular engineering strategy, distinct from previous approaches based on the direct insertion of large cytokine receptor fragments, in which the intracellular CAR signaling domain was reconstructed to incorporate compact IL2/IL15 receptor-derived activation motifs, thereby enabling antigen-dependent coactivation while preserving the overall architecture of the parental CAR. Through systematic screening, we identified S71 as the optimal construct, with significantly greater antitumor activity than other mutants across multiple solid and hematologic tumor targets. Mechanistically, S71 rewired CAR signaling and reprogrammed tumor-induced metabolic responses through a self-sustaining mechanism, improving mitochondrial function and supporting durable T-cell activity. Functionally, S71 promoted enhanced persistence and robust immune memory responses against solid tumors. These findings demonstrate that the modular integration of cytokine signaling motifs into CAR intracellular domains can improve CAR T-cell fitness and antitumor efficacy, and they establish S71 as a promising strategy for overcoming barriers to CAR T-cell therapy in solid tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1272-1291"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147947970","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 Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.","authors":"","doi":"10.1158/2326-6066.CIR-14-8-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-14-8-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"14 8","pages":"1209"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148668490","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":"Multiple Myeloma Cells Resistant to T-cell Therapies Exhibit a CD45+ Immunoevasive Phenotype.","authors":"Alana L Keller, Kady A Dennis, Denis J Ohlstrom, Sarah E Parzych, Zachary J Walker, Amanda J Novak, Catherine Pham-Danis, Tanisha N Medha, Jeremy T Rahkola, Meher P Boorgula, M Eric Kohler, Daniel W Sherbenou","doi":"10.1158/2326-6066.CIR-25-1068","DOIUrl":"10.1158/2326-6066.CIR-25-1068","url":null,"abstract":"<p><p>Multiple myeloma is a plasma cell malignancy that is mostly incurable, even with recent advances in treatment such as B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells and bispecific T cell-engaging (TCE) antibodies. To better understand this treatment resistance, we examined multiple myeloma cells that persisted after these treatments and consistently observed CD45 upregulation as part of a resistance program. Bone marrow samples were treated ex vivo with BCMA CAR T cells, TCE antibodies (elranatamab, SAR442257), or activated T cells and analyzed via flow cytometry. CD45 upregulation was validated in patient samples before and after idecabtagene vicleucel therapy (anti-BCMA CAR T-cell therapy) and using an in vivo mouse model of disseminated multiple myeloma. Persisting multiple myeloma cells exhibited focal CD45 surface patches. Mechanistic studies implicated secreted HSP70, whereas bulk RNA sequencing revealed increased LAG-3, IFNγ signaling, and PD-L1 expression. These findings suggest that T cell-redirecting therapy (TCRT) drives an immunoevasive phenotype defined by CD45 upregulation and immune checkpoint activation, supporting combination strategies of TCRT with checkpoint inhibitors to overcome resistance in relapsed/refractory multiple myeloma.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1307-1321"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13557096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148216607","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":"ILT2 Identifies an Unexploited Pool of Intratumoral CD8+ Bystander T Cells with TCR-Independent Cytotoxicity in Renal Cell Carcinoma.","authors":"Rebecca Laboureur, Clément Dumont, Dzenis Koca, Leonard Lugand, Margaux Bossis, Emilie Artru, Alix Jacquier, Jerome Verine, Fatiha Bouhidel, Malika Djouadou, Alexandra Masson-Lecomte, Jules Russick, Edgardo D Carosella, François Desgrandchamps, Laurent Guyon, Pierre Tonnerre, Joel LeMaoult, Nathalie Rouas-Freiss","doi":"10.1158/2326-6066.CIR-25-1109","DOIUrl":"10.1158/2326-6066.CIR-25-1109","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have improved clear-cell renal cell carcinoma (ccRCC) therapy, yet many patients remain unresponsive. Alternative strategies are needed, and the HLA-G/ILT2 axis has emerged as a promising immunosuppressive pathway. In this study, we deeply characterized CD8+ILT2+ tumor-infiltrating lymphocytes (TIL) as a distinct subset from CD8+PD-1+ TILs in ccRCC, using high-dimensional spectral flow cytometry, single-cell transcriptomics, and T-cell receptor (TCR) clonotype analysis. CD8+ILT2+ TILs were terminally differentiated, highly cytotoxic \"bystander\" cells, enriched for virus-specific TCRs. They phenotypically, transcriptionally, and functionally mirrored their circulating counterparts, suggesting peripheral recruitment. In dynamic coculture assays, they exhibited potent TCR-independent cytotoxicity, mediated by activating innate receptors, namely NKG2D. However, HLA-G inhibited this activity, underscoring the immune-evasive role of the HLA-G/ILT2 axis. Our study defines CD8+ILT2+ TILs as an untapped effector population with potential antitumor activity and a promising therapeutic target in ccRCC. These findings offer new insights into TIL functional diversity and pave the way for innovative immunotherapies beyond conventional ICIs.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1335-1350"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204297","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":"Fueling Immunotherapy Resistance: SSBP4 Links Tumor Cholesterol Biosynthesis to Immune Evasion.","authors":"James Gow, Yibin Kang","doi":"10.1158/2326-6066.CIR-26-0635","DOIUrl":"10.1158/2326-6066.CIR-26-0635","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have had a transformative impact on cancer treatment. However, many patients still fail to respond to ICIs, underscoring the need to identify novel drivers of resistance. In this issue, Ou and colleagues identify single-stranded DNA binding protein 4 (SSBP4) as one such candidate, demonstrating that it promotes intratumoral cholesterol biosynthesis to suppress lymphocyte recruitment and enable immune evasion. This work therefore nominates SSBP4 as a novel metabolic target to enhance antitumor immunity and expand ICI efficacy. See related article by Ou et al., p. 1216.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1210-1211"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343942","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":"DNA Hypomethylating Agents Preserve T-cell Stemness and Potentiate the Efficacy of CD3-Bispecific Antibodies.","authors":"Mark Aleynick, Qingqing Wang, Jennifer E Wu, Samantha Lemus, Matthew Chaimowitz, Hannan Mir, Jacqueline J Warsaw, Chunguang Guo, Lynn E Macdonald, Janelle C Waite, Nikos Kourtis, Dimitris Skokos","doi":"10.1158/2326-6066.CIR-25-1420","DOIUrl":"10.1158/2326-6066.CIR-25-1420","url":null,"abstract":"<p><p>Bispecific antibodies targeting tumor-associated antigens and CD3 are promising therapeutic agents for both solid and hematologic cancers. CD3-bispecifics induce T-cell activation and cytotoxicity; however, prolonged T-cell receptor (TCR) stimulation can lead to chromatin rewiring and T-cell dysfunction, thereby limiting their full therapeutic potential. In this study, we investigate the combination of CD3-bispecifics with the DNA hypomethylating agent decitabine (DAC) and observe enhanced tumor growth inhibition in various preclinical models. Utilizing a prostate-specific membrane antigen (PSMA)×CD3 bispecific antibody for the treatment of prostate carcinoma and in vivo humanized mouse disease models, we catalog, at the single-cell level, the dynamics of T-cell epigenetic states during bispecific therapy and in combination with DAC. Importantly, this combination strategy preserves a T-cell factor 1 (TCF-1)-positive T-cell population and delays acquisition of a dysfunctional state at both chromatin and protein levels. At the DNA methylation level, TCR stimulation in the presence of DAC maintains a naïve-like pattern in gene loci associated with T-cell stemness. This study provides a resource for understanding the evolution of T-cell states during immunotherapy and mechanistic support for combining epigenetic modifiers with CD3-bispecifics in the clinic.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1322-1334"},"PeriodicalIF":7.9,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13434290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223202","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}