Journal for Immunotherapy of Cancer最新文献

{"title":"NKG2A-HLA-E axis contributes to an immunosuppressive checkpoint network in hepatocellular carcinoma.","authors":"Yan Li, Xiaomei Zhuang, Yisen Tang, Wanhua Feng, Yingzi Huang, Zhu Li, Yuanyu Lin, Di Tang, Gang Deng, Songlin Peng, Wei Qin, Zubing Chen, Xiaoying Wu, Ze Song, Patrick P C Boor, Sonja I Buschow, Dave Sprengers, Guoying Zhou","doi":"10.1136/jitc-2026-015639","DOIUrl":"10.1136/jitc-2026-015639","url":null,"abstract":"<p><strong>Background: </strong>The immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) limits the efficacy of current immunotherapies. The interplay between the emerging inhibitory receptor NKG2A and its activating counterpart NKG2C, both binding HLA-E, and its interaction with the PD-1-PD-L1 pathway in cancer remains unclear. This study aims to delineate the functional network formed by these pathways in shaping the immunosuppressive landscape of HCC.</p><p><strong>Methods: </strong>We analyzed public databases and performed immunohistochemistry on HCC tissues to assess HLA-E expression and prognostic relevance. Tumor-infiltrating lymphocytes from patient samples were examined by flow cytometry to evaluate the functional impact of NKG2A, NKG2C, and PD-1 expression on T and NK cells. Single-cell RNA and T cell receptor (TCR) sequencing were employed to characterize immune subset heterogeneity. Functional assays and mouse models were used to evaluate the effects of NKG2A and PD-1 blockade.</p><p><strong>Results: </strong>In the absence of CD8⁺ T cell infiltration, elevated HLA-E expression in HCC tissue correlated with poorer overall survival in non-immunotherapy-treated patients. Conversely, in the presence of CD8⁺ T cells, high HLA-E expression was linked to an inflammatory tumor microenvironment characterized by IFN-γ-producing T cells, and increased major histocompatibility complex I, which was associated with improved patient response to immunotherapy. Tumor-infiltrating CD8⁺ T and NK cells from HCC patients upregulated NKG2A, conferring tissue-resident memory and tumor-reactive characteristics while simultaneously impairing cytotoxic function. Single-cell RNA and TCR sequencing revealed differential expression patterns of NKG2A, NKG2C, and PD-1 in different T and NK cell subsets, with NKG2A⁺ PD-1⁺ T cells relevant to antigen-specific clonal expansion. Mechanistically, the inhibitory effect mediated by the NKG2A-HLA-E axis contributed more prominently than the stimulatory role of the NKG2C-HLA-E axis in suppressing antitumor immunity. Furthermore, the NKG2A-HLA-E axis acted cooperatively with the PD-1-PD-L1 axis to promote CD8⁺ T cell dysfunction. Combined blockade of NKG2A and PD-1 enhanced the cytotoxic activity of tumor-infiltrating CD8⁺ T and NK cells, resulting in potent tumor eradication in vitro and in vivo, outperforming single-agent treatments.</p><p><strong>Conclusions: </strong>Our findings identify the NKG2A-HLA-E axis as an important immunoregulatory pathway associated with immune suppression in HCC and provide a rationale for further evaluation of combined NKG2A and PD-1 blockade strategies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017013","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":"Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of acute leukemia, version 2.0.","authors":"Nirali N Shah, Charles Craddock, Lia Gore, Monica L Guzman, Elias Jabbour, Alexandra R Lovell, Katia Luciani, Ravindra Majeti, Shannon L Maude, Miguel-Angel Perales, Michael A Pulsipher, David A Sallman, Bijal D Shah, Wendy Stock, Marion Subklewe, Sarah K Tasian, Brent L Wood, Bonnie Yates, Naval Daver","doi":"10.1136/jitc-2026-015963","DOIUrl":"10.1136/jitc-2026-015963","url":null,"abstract":"<p><p>Acute leukemia is a hematologic malignancy that affects people of all ages. Immunotherapies, including T-cell engagers, antibody-drug conjugates, and chimeric antigen receptor T-cell therapies have contributed to a paradigm shift in the treatment of patients with acute leukemia. Combined with advancements in allogeneic hematopoietic stem cell transplant and targeted therapy development, patients with acute leukemia have additional effective treatment options, providing the possibility of long-term remission. However, these advances have resulted in a complex and dynamic treatment landscape for clinicians to navigate. To guide the oncology community and provide a framework for patient care, the Society for Immunotherapy of Cancer convened a panel of experts to develop this clinical practice guideline on immunotherapy for the treatment of acute leukemia. Drawing from published data and clinical experience, the Expert Panel developed evidence-based and consensus-based recommendations relating to diagnostics; immunotherapies for the treatment of acute lymphoblastic leukemia, acute myeloid leukemia, and blastic plasmacytoid dendritic cell neoplasm; toxicity and safety management; treatment sequencing; and patient education and quality of life.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016976","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":"Phase 1 study of KHK2455, a long-acting, potent and selective IDO1 inhibitor, in combination with avelumab in patients with locally advanced or metastatic urothelial carcinoma.","authors":"Yousef Zakharia, Bernard Doger de Spéville, Rafael Morales-Barrera, Irene Moreno, Deepak Kilari, Julio Peguero, Santosh Rao, Lisa H Shiue, Hironori Kanda, Yi Liu, Payal Arora, Ragini Vuppugalla, Alejo Rodriguez-Vida","doi":"10.1136/jitc-2026-015178","DOIUrl":"10.1136/jitc-2026-015178","url":null,"abstract":"<p><strong>Background: </strong>Dual inhibition of indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death-ligand 1 (PD-L1) may alleviate suppression of antitumor immune responses by overcoming redundant immunosuppressive pathways. This study evaluated the combination of KHK2455, a novel and selective, long-lasting, and potent oral IDO1 inhibitor, with avelumab, a PD-L1 inhibitor, in adults with locally advanced or metastatic urothelial carcinoma.</p><p><strong>Methods: </strong>This multicenter, open-label Phase 1 study evaluated the safety and tolerability of oral daily KHK2455 (30, 100, and 200 mg) plus intravenous avelumab (800 mg biweekly), the safety of KHK2455 200 mg monotherapy, KHK2455 and avelumab antitumor activity, avelumab antidrug antibodies, and combination therapy pharmacokinetics.</p><p><strong>Results: </strong>16 subjects were enrolled (n=4, 4, and 8 in the 30, 100 and 200 mg cohorts, respectively). No dose-dependency was observed for KHK2455-only related treatment-emergent adverse events (TEAEs). No TEAEs were considered related to KHK2455 or avelumab. Four subjects had fatal TEAEs considered not related to treatment.One subject in the KHK2455 30 mg cohort achieved a complete response (CR) and one in the KHK2455 200 mg cohort achieved a partial response (PR), both with avelumab.PD-L1 expression was evaluated in the 13 available baseline tumor biopsy samples. All biopsies expressed PD-L1 in at least one compartment; 31% (4/13) were positive on tumor cells and 69.2% (9/13) were positive on tumor-associated immune cells. Over half (53.8%, 7/13) expressed PD-L1 at high levels and within the disease control group consisting of CR (n=1), PR (n=1) and stable disease (n=5), 57.1% (4/7) were PD-L1 high. Baseline expression profiles showed significantly higher immune activation in the subject with CR compared with the subject with PR and those with progressive disease. The subject with CR had the highest baseline Tumor Inflammation Signature (TIS) score (9.06) compared with 4.8 in the subject with PR and lower TIS score values in subjects with progressive disease. Changes in gene expression were observed, including upregulation of CXCL12, CCND2, and MMRN2, and downregulation of HLA-DRB5, CRABP2, and VEGFA in responders versus progressive disease comparisons.</p><p><strong>Conclusions: </strong>The favorable safety profile and preliminary efficacy results of KHK2455 in combination with avelumab, along with the translational biomarker findings, warrant further investigation.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149017001","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":"Gene regulatory elements determine efficacy of BCMA-targeted CAR-T cell products.","authors":"Viktoria Blumenberg, Kristen B June, Filippo Birocchi, Giulia Escobar, Charlotte Graham, Yueyang Fan, Merle K Phillips, Sangwoo Park, Deshea Harris, Henry Anderson, Amanda A Bouffard, Christopher Kelly, Magdi Elsallab, Trisha R Berger, Kathleen Me Gallagher, Mark B Leick, Adele Mucci, Marcela V Maus","doi":"10.1136/jitc-2026-016839","DOIUrl":"10.1136/jitc-2026-016839","url":null,"abstract":"<p><p>In relapsed/refractory multiple myeloma, the approved B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cell product ciltacabtagene autoleucel (cilta-cel) shows higher response rates than idecabtagene vicleucel (ide-cel) in pivotal trials and real-world comparisons. This advantage has been attributed to the biparatopic dual-VHH (dVHH) binder of cilta-cel. However, the products also differ in the gene regulatory elements driving CAR expression: cilta-cel uses a human elongation factor α (EF1α) promoter in conjunction with a woodchuck hepatitis post-transcriptional regulatory element (EF1α^+WPRE), whereas ide-cel uses a myeloproliferative sarcoma virus enhancer (MND) promoter without WPRE (MMD^-WPRE). The role of these elements in CAR-T cell efficacy remains unexplored.We generated lentiviral vectors where the CAR transgene was composed of either a dVHH-based or a single-chain variable fragment (scFv)-based BCMA-CAR with a 4-1BB costimulatory and a CD3ζ signaling domain, expressed either by EF1α^+WPRE or MND^-WPRE Primary human T cells or a nuclear factor of activated T cells (NFAT)-GFP Jurkat reporter line were compared at matched vector copy numbers (VCN) or CAR surface expression. Antitumor efficacy was assessed in MM.1S-engrafted NSG mice.When transduced at the same multiplicities of infection, MND^-WPRE CAR-T cells reached higher VCN and transduction rates than EF1α^+WPRE regardless of the binder type. In an NFAT-GFP reporter assay, unstimulated MND^-WPRE-driven cells showed higher NFAT and CD69 expression, consistent with greater tonic signaling compared with EF1α^+WPRE In vivo, independently of the BCMA binder moiety, EF1α^+WPRE-driven CAR-T cells demonstrated superior cytokine secretion and tumor control along with greater survival of mice treated with EF1α^+WPREcompared with MND^-WPRE-driven CAR-T cells.CAR-T cells expressing the CAR under MND^-WPRE showed greater gene transfer during manufacturing, but this did not translate into superior function in vivo. The advantage attributed to cilta-cel's dual VHH binder was lost when expressed under MND^-WPRE and, conversely, ide-cel's scFv binder achieved better antitumor activity when expressed under EF1α^+WPRE than under MND^-WPRE The efficacy difference between our CAR constructs in xenograft models therefore tracked with the choice of regulatory elements driving CAR expression independently of the binder. It may be better to choose gene regulatory elements based on the CAR-T cell function they confer rather than on expression strength alone.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001940","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":"Frailty of older patients is not reflected in the melanoma tumor microenvironment and treatment response to immune checkpoint blockade therapy.","authors":"Asli Özkan, Marieke IJsselsteijn, Ziena Abdulrahman, Manon van der Ploeg, Ellen Kapiteijn, Marije Slingerland, Els M E Verdegaal, Marij J P Welters, Sjoerd H van der Burg, Johanneke E A Portielje, Noel F C C de Miranda, Nienke A de Glas","doi":"10.1136/jitc-2026-015212","DOIUrl":"10.1136/jitc-2026-015212","url":null,"abstract":"<p><p>Older adults with frailty demonstrate systemic immunosenescence, including T-cell exhaustion and reduced immune diversity, yet maintain immune checkpoint blockade (ICB) efficacy comparable to that of younger patients. Baseline immune cell composition in both the tumor microenvironment (TME) and peripheral blood has been linked to ICB response in melanoma. To address this paradox, we investigated whether frailty is associated with alterations in the TME immune composition in melanoma.We applied imaging mass cytometry with a 40-marker panel to comprehensively characterize the pretreatment immune TME in formalin-fixed, paraffin-embedded tissue from 23 patients with melanoma, stratified by age, frailty status (as determined by the Clinical Frailty Scale), and clinical benefit from ICB. 33 immune cell phenotypes were identified and compared across patient groups.Frail patients exhibited significantly higher densities of CD4⁺CD45RO⁺ memory T cells compared with non-frail older patients. No other differences in the immune TME were observed between frail and non-frail patients, and overall survival was comparable between these groups. In contrast, multiple age-related differences were observed, including reduced naive T-cell densities and increased myeloid cell infiltration in older patients, consistent with features of immunologic aging. Clinical benefit from ICB was associated with greater overall immune infiltration and lower granulocyte densities, independent of age or frailty status.Despite previously demonstrated systemic immunosenescence, the melanoma immune TME preserved in older adults with frailty, consistent with observed preservation of ICB efficacy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599837/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001975","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":"CT-based deep foundation model for predicting immune checkpoint inhibitor-induced pneumonitis risk in lung cancer.","authors":"Amgad Muneer, Eman Showkatian, Yuliya Kitsel, Maliazurina B Saad, Sheeba J Sujit, Felipe Soto, Girish S Shroff, Saadia A Faiz, Mohammad I Ghanbar, Sherif M Ismail, Natalie I Vokes, Tina Cascone, Xiuning Le, Jianjun Zhang, Lauren A Byers, David Jaffray, Joe Y Chang, Zhongxing Liao, Aung Naing, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Karthik Suresh, Mehmet Altan, Ajay Sheshadri, Jia Wu","doi":"10.1136/jitc-2026-015014","DOIUrl":"10.1136/jitc-2026-015014","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but can cause serious immune-related adverse events, with pneumonitis (ICI-P) being among the most severe. Early identification of high-risk patients before ICI initiation is critical for close monitoring, timely intervention, and optimizing outcomes.</p><p><strong>Purpose: </strong>To develop and validate a deep learning foundation model to predict ICI-P from baseline CT scans in patients with lung cancer.</p><p><strong>Methods: </strong>We designed the Checkpoint-Inhibitor Pneumonitis Hazard EstimatoR (CIPHER), a deep learning-powered foundation model combining contrastive learning with a transformer-based masked autoencoder to predict ICI-P from baseline CT scans in patients with lung cancer. Using self-supervised learning, CIPHER was pretrained on 590,284 CT slices from 2,500 patients with non-small cell lung cancer (NSCLC) to learn representations of heterogeneous lung parenchyma. Following pretraining, CIPHER was adapted to the internal MD Anderson Cancer Center NSCLC immunotherapy cohort of 347 patients, of whom 33 developed adjudicated ICI-P. Fine-tuning was performed using 254 non-ICI-P patients only, and a held-out internal validation set of 93 patients, including 33 ICI-P cases and 60 non-ICI-P controls, was reserved for evaluation. CIPHER was benchmarked against clinical, radiomics, and ensemble comparator models and externally validated in an independent Johns Hopkins NSCLC cohort of 116 patients, including 20 ICI-P cases and 96 non-ICI-P controls.</p><p><strong>Results: </strong>In our internal immunotherapy cohort, CIPHER consistently distinguished patients at elevated risk of ICI-P from those without the event, with area under the curves (AUCs) ranging from 0.77 to 0.85. In head-to-head benchmarking, CIPHER achieved an AUC of 0.83, outperforming the clinical, radiomics and ensemble models. In the external validation cohort, CIPHER maintained high performance (AUC=0.83; balanced accuracy=81.7%), exceeding the radiomics model (DeLong p=0.0318) and demonstrating superior specificity without sacrificing sensitivity. By contrast, the radiomics model, despite high sensitivity (85.0%), showed markedly lower specificity (45.8%). Confusion matrix analyses confirmed CIPHER's robust classification, correctly identifying 80 of 96 non-ICI-P cases and 16 of 20 ICI-P cases.</p><p><strong>Conclusions: </strong>We developed and externally validated CIPHER, a CT-based imaging biomarker for pretreatment ICI-P risk stratification in NSCLC. CIPHER shows promise as a non-invasive tool for ICI-P risk assessment but warrants prospective validation before clinical translation.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001882","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":"CD28-ICOS costimulation enhances the therapeutic efficacy of L1CAM-targeted CAR-T cells against ovarian and gastric cancers.","authors":"Xiumei Che, Un-Jung Yun, Junsub Lee, Hyun-Hee Koh, Ju-Yeon Lee, Jungmin Jeon, Subin So, Youngyoub Kim, Jin-A Chae, Xianglan Zhang, Hyoyoung Kim, Jiwoo Hwang, Eunhyang Park, Eun Ji Nam, Gun Min Kim, Minkyu Jung","doi":"10.1136/jitc-2025-014131","DOIUrl":"10.1136/jitc-2025-014131","url":null,"abstract":"<p><strong>Background: </strong>Ovarian and gastric cancers are associated with poor prognosis and derive limited benefit from current therapies, highlighting the need for novel immunotherapeutic approaches. The L1 cell adhesion molecule (L1CAM) is aberrantly expressed in several types of solid tumors and is associated with aggressive clinical behavior. This study aimed to develop and characterize optimized L1CAM-targeted chimeric antigen receptor-T (CAR-T) cells with improved efficacy and safety, using patient-derived preclinical models of ovarian and gastric cancer.</p><p><strong>Methods: </strong>L1CAM expression was assessed in tumor tissues from patients with ovarian cancer (OC;n=227) and gastric cancer (GC;n=132), followed by an analysis of its clinical impact. A panel of L1CAM-targeted CAR constructs incorporating distinct hinge and co-stimulatory domains was systematically evaluated. Functional activity was assessed by cytotoxicity and cytokine release assays using cancer cell lines and patient-derived tumor cells. Antitumor efficacy, persistence, and safety were evaluated in xenograft and patient-derived xenograft (PDX) models, including NanoLuc-based in vivo tracking of CAR-T cell distribution.</p><p><strong>Results: </strong>High L1CAM expression correlated with aggressive clinicopathological features and adverse prognosis in patients with OC. Among the constructs tested, CAR-T cells incorporating an IgD/IgG1 hybrid hinge and dual CD28-ICOS co-stimulatory domains demonstrated the most potent antigen-specific activity. These cells exhibited enhanced cytotoxicity, robust interferon-γ production, and sustained functional activity. In vivo, optimized L1CAM CAR-T cells achieved complete tumor regression in OC PDX models and significant tumor suppression in GC models, with durable tumor control and CAR-T persistence. Intraperitoneal delivery further improved therapeutic efficacy and CAR-T cell localization compared with intravenous administration. Importantly, no evidence of neurotoxicity or systemic toxicity was observed, supporting a favorable safety profile.</p><p><strong>Conclusions: </strong>Optimized L1CAM-targeted CAR-T cells demonstrate potent, durable, and antigen-specific antitumor activity with a favorable safety profile in preclinical models of OC and GC. The combination of rational CAR design (CD28-ICOS signaling) and optimized delivery strategy provides a strong rationale for the clinical development of L1CAM-targeted CAR-T therapy, particularly in patients with L1CAM-positive solid tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149001830","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":"IgM promotes antitumor immunity to a Tn-expressing solid tumor.","authors":"Hope L Nzuki, Jamie E Jennings-Gee, Michaela Trivette, Timothy H Mosher, Alexis E Adams-Sims, Abigail A Hegarty, Karen M Haas","doi":"10.1136/jitc-2026-015127","DOIUrl":"10.1136/jitc-2026-015127","url":null,"abstract":"<p><strong>Background: </strong>Altered O-glycosylation is a hallmark of many adenocarcinomas and is often characterized by expression of the Tn antigen. However, the role of B cells in protection against Tn-expressing solid tumors remains poorly understood.</p><p><strong>Methods: </strong>We generated a colorectal tumor cell line (CMT93) lacking <i>Cosmc</i>, resulting in high Tn expression. Using mice with defined B-cell abnormalities, including deficiencies in B cells, IgM secretion, natural IgM, and B-cell receptor (BCR) repertoire diversity, we investigated the contribution of B cells and secreted antibody to immunity against Tn-expressing colorectal tumors.</p><p><strong>Results: </strong><i>Cosmc</i>-deficient tumors grew more rapidly than parental tumors, and IgM deposition was observed within tumors from wild-type mice, suggesting a potential role for antibody in antitumor defense. Tumor-reactive serum IgM, including Tn-reactive IgM, was present in naïve mice. B cell-deficient muMT, V_HB_1-8 transgenic mice with a restricted BCR repertoire, CD19^-/- mice deficient in natural IgM, and μS^-/- mice unable to secrete IgM, lacked tumor-reactive IgM and showed increased tumor burdens, suggesting a protective role for secreted tumor-reactive IgM. Lack of tumor-reactive IgM in V_HB_1-8 transgenic and μS^-/- mice was associated with significant alterations in tumor-infiltrating leukocyte composition. Relative to wild-type mice, tumors from V_HB_1-8 transgenic and μS^-/- mice exhibited significantly increased PD-L1^hiLy6G⁺Ly6C^-CD11b⁺ myeloid cells, but reduced B, T, and natural killer cells, along with reduced major histocompatibility complex class II expression on tumor-associated dendritic cells. Moreover, tumor draining lymph nodes from V_HB_1-8 transgenic and μS^-/- mice showed significant reductions in antibody-secreting cells, including IgG⁺ plasmablasts, which corresponded with decreased IgM and IgG deposition on tumors.</p><p><strong>Conclusions: </strong>These findings support a role for B cells and secreted IgM in restraining the growth of Tn-expressing solid tumors and shaping antitumor immunity against tumors with aberrant O-glycosylation.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13599870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148990102","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":"LRIG2 suppresses NK cell-induced GSDME-mediated pyroptosis via the LAMP1-STAT3 pathway in glioma.","authors":"Xiaoshuang Hou, Lan Lin, Po Zhang, Youwei Li, Minhai Dong, Sui Chen, Xiaohu Oyang, Jingbo Wang, Fangling Cheng, Xiaopeng Li, Min Zhao, Feng Mao, Xingjiang Yu, Desheng Hu, Baofeng Wang, Dongsheng Guo","doi":"10.1136/jitc-2026-015730","DOIUrl":"10.1136/jitc-2026-015730","url":null,"abstract":"<p><strong>Background: </strong>Gliomas are resistant to current therapies, and natural killer (NK) cell-based immunotherapy shows limited efficacy. Gasdermin E (GSDME)-mediated pyroptosis contributes to NK-induced tumor killing, but NK cell dysfunction in the glioma microenvironment remains poorly understood. This study investigates whether leucine-rich repeats and immunoglobulin-like domains 2 (LRIG2) enable glioma cells to evade NK-induced pyroptosis and elucidates the underlying mechanism.</p><p><strong>Methods: </strong>We used in vitro co-culture systems with glioma cell lines (LN229, HS683, FU) and primary NK cells or NK92-MI cells to assess cytotoxicity, pyroptosis (lactate dehydrogenase release, morphology, GSDME cleavage by western blot), and cytokine release (Cytometric Bead Array). In vivo, orthotopic glioma models in C57BL/6 and RAG1-KO mice received intracranial stimulator of interferon genes agonist diABZI. Mechanistic dissection involved biochemical approaches (co-immunoprecipitation-mass spectrometry and membrane protein extraction), cellular imaging (immunofluorescence), and genetic perturbation via CRISPR-mediated knockdown.</p><p><strong>Results: </strong>NK cells induced GSDME-dependent pyroptosis in glioma cells in vitro, but this was impaired in vivo due to suppressed NK cytotoxicity. LRIG2 was highly expressed in gliomas; its overexpression inhibited GSDME cleavage, pyroptosis, and glioma cell death, whereas LRIG2 knockdown enhanced these effects. Mechanistically, soluble LRIG2 shed from glioma cells bound to lysosomal-associated membrane protein 1 (LAMP1) on NK cells, upregulating phosphorylated-signal transducer and activator of transcription (p-STAT3) via Janus kinase 1 (JAK1) and reducing granzyme B and perforin release. Disrupting the LRIG2-LAMP1-STAT3 axis by LRIG2 knockdown or STAT3 knockout restored NK cytotoxicity and GSDME cleavage. Combining LRIG2 knockdown with diABZI significantly enhanced NK granzyme B expression and prolonged mouse survival.</p><p><strong>Conclusions: </strong>LRIG2 enables glioma immune evasion by suppressing NK-induced GSDME-mediated pyroptosis via the LAMP1-STAT3 pathway. Targeting this axis represents a promising strategy to enhance NK cell-based immunotherapy for gliomas, positioning LRIG2 as a potential biomarker and therapeutic target.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148976842","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":"Epigenetic plus cytokine therapy induces stem-like CD8⁺ T-cell reservoirs and intratumoral immune niches to overcome anti-PD-1 resistance.","authors":"Christine Mall Minnar, Masaya Miyamoto, Asma Sarah Khelifa, Grace Lui, Katherine E Lothstein, Ainara Meler, Maria Del Mar Maldonado, Duane H Hamilton, Lisa K Poppe, Nicholas Roller, Kenneth Canubas, George Zaki, Wiem Lassoued, Alexei Lobanov, Darryl Nousome, Richard Finney, Margaret Cam, Patrick Soon-Shiong, James L Gulley, Jeffrey Schlom, Sofia R Gameiro","doi":"10.1136/jitc-2026-015228","DOIUrl":"10.1136/jitc-2026-015228","url":null,"abstract":"<p><strong>Background: </strong>Checkpoint blockade (CPB) has limited efficacy in patients with colorectal cancer (CRC), warranting improved therapeutic strategies capable of remodeling the tumor microenvironment. Stem-like TCF1⁺CD8⁺ T cells, cytotoxic CD8⁺ T cells, and lymphoid aggregates have been associated with CPB responsiveness, either individually or as coordinated immune hubs.</p><p><strong>Methods: </strong>We evaluated the combination of αPD-1, the class I histone deacetylase inhibitor entinostat, and the IL-15 superagonist N-803 in CPB-resistant murine CRC and breast cancer models with varying antigen presentation deficiencies. Proteomic, transcriptomic, spatial, and functional analyses were completed to identify treatment-specific immune remodeling. Translational relevance was assessed using publicly available CPB-treated cancer genomic datasets and functional assays with patient-derived peripheral blood mononuclear cells (PBMCs).</p><p><strong>Results: </strong>Triple therapy increased stem-like TCF1⁺CD8⁺ T cells in tumor-draining lymph nodes and tumors, concomitant with increased intratumoral cytotoxic GZMB⁺CD8⁺ T cells. Therapeutic efficacy was associated with remodeling of the tumor microenvironment, uniquely marked by enrichment of intratumoral immune niches comprising TCF1⁺ and cytotoxic CD8⁺ T cells, type 1 conventional dendritic cells, and B cells, along with concerted cytokine and chemokine production. A transcriptional signature derived from triple therapy-induced immune niches predicted favorable clinical responses across multiple CPB-experienced cancer cohorts. These responses were functionally corroborated by increased markers of cytotoxicity in patient-derived PBMCs in vitro.</p><p><strong>Conclusions: </strong>Treatment with entinostat, N-803, and αPD-1 boosts anti-tumor intratumoral immune niches comprising TCF1⁺CD8⁺ T cells. Collectively, these findings suggest that TCF1⁺CD8⁺ T cell immune niches previously associated with αPD-1 responsiveness and lacking in non-responders, including most CRC patients, may be restored by the addition of entinostat and N-803 to αPD-1 therapy to treat αPD-1-refractory patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"14 9","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13583839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148955254","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}