Journal for Immunotherapy of Cancer最新文献

{"title":"Correction: Unique immune characteristics and differential anti-PD-1-mediated reinvigoration potential of CD8+ TILs based on BRCA1/2 mutation status in epithelial ovarian cancers.","authors":"","doi":"10.1136/jitc-2024-009058corr1","DOIUrl":"10.1136/jitc-2024-009058corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608401","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":"Malevolent alliance of MYBL2^hi cancer stem cell and SPP1+ macrophage confers resistance to neoadjuvant immunotherapy in bladder cancer.","authors":"Hualin Chen, Zhaoheng Jin, Yueqiang Peng, Yingjie Li, Ziyi Li, Xuebin Zhang, Yi Xie, Jie Dong, Lin Ma, Zhigang Ji","doi":"10.1136/jitc-2024-011319","DOIUrl":"10.1136/jitc-2024-011319","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant immune checkpoint blockade (nICB) has revolutionized cancer treatment, yet the underlying mechanisms of resistance in bladder cancer remain to be explored.</p><p><strong>Methods: </strong>We conducted single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells, tumor tissues, adjacent normal tissues, and metastatic lymph nodes from 2 nICB-naïve and 10 nICB-treated patients with bladder cancer (5 responders and 5 non-responders). Spatial RNA sequencing was performed on tumor slides from two responders and four non-responders. Findings were validated by multiplex immunohistochemistry, mice orthotopic bladder cancer model, and flow cytometry assays.</p><p><strong>Results: </strong>nICB remodeled the tumor microenvironment of bladder cancer from both single-cell and spatial perspectives. scRNA-seq analysis revealed a significant increase in MYBL2^hi cancer stem cells (CSCs) among non-responders. Analysis of the myeloid population showed that SPP1+ macrophages associated with angiogenesis were linked to CD8+ T cell exclusion. Further investigation into cell-cell communication revealed a propensity for bidirectional crosstalk between MYBL2^hi CSCs and SPP1+ macrophages in non-responders. MYBL2^hi CSCs derived CCL15, which bound to CCR1 and induced SPP1 upregulation in macrophages which reciprocally enhanced bladder cancer stemness and resistance to nICB through the SPP1-ITGα9β1 axis. Additionally, we identified an aged CCL3+ neutrophil population that interacted with SPP1+ macrophages through a positive feedback loop, contributing to nICB resistance. Finally, in vivo studies demonstrated that combined MYBL2 knockdown and SPP1 targeting synergistically enhanced ICB efficacy in bladder cancer.</p><p><strong>Conclusions: </strong>Our research reveals transcriptomic characteristics associated with distinct therapeutic responses to nICB treatment, offering a foundation for optimizing personalized neoadjuvant strategies in bladder cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608403","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":"Correspondence on \"METTL3 promotes an immunosuppressive microenvironment in bladder cancer via m6A-dependent CXCL5/CCL5 regulation\" by Tong <i>et al</i>.","authors":"Jiaren Pan, Gang-Fu Zheng, Xin Rui","doi":"10.1136/jitc-2025-012565","DOIUrl":"10.1136/jitc-2025-012565","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600464","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-expression signature predicts autoimmune toxicity in metastatic melanoma.","authors":"Domenico Mallardo, Mario Fordellone, Michael Bailey, Andrew White, Ester Simeone, Lucia Festino, Vito Vanella, Claudia Trojaniello, Maria Grazia Vitale, Margaret Ottaviano, Mariaelena Capone, Caterina Costa, Maria Ingenito, Francesca Sparano, Bianca Arianna Facchini, Ernesta Cavalcanti, Rosaria De Filippi, Corrado Caracò, Alessandra Cesano, Sarah Warren, Paolo Chiodini, Alfredo Budillon, Paolo A Ascierto","doi":"10.1136/jitc-2024-011315","DOIUrl":"10.1136/jitc-2024-011315","url":null,"abstract":"<p><strong>Objectives: </strong>To identify predictive gene-expression signatures for immune-related adverse events (irAEs) in patients with melanoma treated with anti-PD-1 inhibitors, in the adjuvant therapy (AT) and first-line therapy (FLT).</p><p><strong>Methods: </strong>This retrospective study analyzed baseline whole-blood gene expression profile from 161 patients with resected stage III or unresectable stage III-IV melanoma treated with anti-PD-1 inhibitors. RNA was extracted from baseline peripheral blood samples and profiled using the NanoString nCounter PanCancer IO 360 panel. Gene-expression signatures were identified and validated using cross-validated sparse partial least squares modeling and principal component analysis, then correlated with toxicity occurrence.</p><p><strong>Results: </strong>A total of 223 and 186 irAEs were observed in the AT and FLT groups, respectively, including arthralgia, colitis, and headache. Distinct gene-expression signatures significantly predicted toxicity occurrence, with variation across therapy settings. Arthralgia was predicted by immune-related and apoptotic gene signatures (eg, SMAD5, FASLG in FLT; ICOS, TGFB2 in AT), while colitis was linked to inflammatory and adhesion-related pathways. In the AT group, headache was associated with genes involved in interferon and adhesion signaling. Across both cohorts, specific signatures predicted overall irAE risk and timing. No events were observed in patients with low-risk signatures over the follow-up period. In the FLT cohort, arthralgia and cutaneous toxicities were positively associated with ORR, while arthralgia, asthenia, colitis, fatigue, and skin-related toxicities correlated with improved disease control rate. No significant association between irAEs and relapse risk was observed in the adjuvant cohort.</p><p><strong>Conclusions: </strong>Whole-blood gene-expression profiling enables early identification of patients at high risk for irAEs during anti-PD-1 therapy. These predictive biomarkers may guide personalized toxicity monitoring in melanoma treatment.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600465","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":"Therapeutic potential of targeting LAG-3 in cancer.","authors":"Diwakar Davar, Ana Carrizosa Anderson, Ivan Diaz-Padilla","doi":"10.1136/jitc-2025-011652","DOIUrl":"10.1136/jitc-2025-011652","url":null,"abstract":"<p><p>Immune checkpoint inhibitors targeting negative regulatory checkpoints including programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 have produced significant improvements in progression-free survival (PFS) and overall survival in multiple solid tumors. Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that is highly expressed by exhausted T cells. Dual blockade of LAG-3 and PD-1 with monoclonal antibodies relatlimab and nivolumab has improved PFS in advanced melanoma, leading to Food and Drug Administration approval for this indication. Concurrently, enthusiasm for targeting LAG-3 has been tempered by negative results in multiple indications, although novel approaches including LAG-3-directed bispecifics tebotelimab continue to demonstrate promise. In this review, we discuss the current understanding of LAG-3 in regulating antitumor immunity and the ongoing state of clinical development of LAG-3-directed agents in cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600477","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":"Precision targeting of rhabdomyosarcoma by combining primary CAR NK cells and radiotherapy.","authors":"Lisa Marie Reindl, Lida Jalili, Tobias Bexte, Sabine Harenkamp, Sophia Thul, Stephanie Hehlgans, Alina Wallenwein, Florian Rothweiler, Jindrich Cinatl, Martin Michaelis, Halvard Bonig, Elise Gradhand, Meike Vogler, Franz Rödel, Winfried S Wels, Evelyn Ullrich","doi":"10.1136/jitc-2024-011330","DOIUrl":"10.1136/jitc-2024-011330","url":null,"abstract":"<p><p><b>Background:</b> Rhabdomyosarcoma (RMS) is the most common type of soft-tissue sarcoma in children, and it remains a challenging cancer with poor outcomes in high-risk and metastatic patients. This study reports the use of epidermal growth factor receptor (EGFR)-targeted chimeric antigen receptor (CAR) natural killer (NK) cells in combination with radiotherapy as a novel immunotherapeutic approach for RMS treatment.<b>Methods:</b> Primary human NK cells from healthy donors were engineered using lentiviral transduction to express a cetuximab-based EGFR-specific CAR. The ability of the engineered NK cells to lyse RMS cells was then assessed in vitro in RMS monolayers and spheroids, as well as against chemotherapy-resistant and primary patient-derived RMS cells. Migratory properties of NK cells were observed in a subcutaneous RMS xenograft model using in vivo imaging, and the efficacy of EGFR-CAR NK cells in combination with localized fractionated radiotherapy was analyzed.<b>Results:</b> Primary human EGFR-CAR NK cells demonstrated enhanced cytotoxicity against multiple RMS cell lines in both two-dimensional culture and three-dimensional spheroid models. Furthermore, EGFR-CAR NK cells were highly efficient against chemotherapy-resistant RMS cells and patient-derived samples. Importantly, EGFR-CAR NK cells also exhibited improved tumor homing compared with non-transduced NK cells in an in vivo RMS xenograft model. Notably, the combination of EGFR-CAR NK cell therapy with fractionated radiotherapy further enhanced NK cell infiltration into the tumor and reduced tumor growth.<b>Conclusion:</b> This study provides a proof-of-concept for EGFR-CAR NK cells as a promising immunotherapy for RMS, particularly when combined with radiotherapy to overcome barriers of solid tumors. This combinatorial approach may hold potential to improve outcomes for patients with RMS and other EGFR-expressing malignancies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232460/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583913","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":"Authors response to \"Letter to the Editor\": \"Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types\".","authors":"Ryon P Graf, David R Gandara","doi":"10.1136/jitc-2025-012334","DOIUrl":"10.1136/jitc-2025-012334","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12258321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583910","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":"Oncolytic HSV-IL27 expression improves CD8 T cell function and therapeutic activity in syngeneic glioma models.","authors":"Alexia K Martin, Jack Hedberg, Ilse Hernandez-Aguirre, Uksha Saini, Doyeon Kim, Yeaseul Kim, Ravi Dhital, Kevin A Cassady","doi":"10.1136/jitc-2025-012227","DOIUrl":"10.1136/jitc-2025-012227","url":null,"abstract":"<p><strong>Background: </strong>Malignant gliomas (MGs) are the most common primary brain malignancies and are considered universally fatal. Oncolytic herpes simplex viruses (oHSVs) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting antitumor immunity, and providing local delivery of immune-activating transgenes. Interleukin 27 (IL-27) is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T lymphocyte (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve antiglioma therapeutic activity.</p><p><strong>Methods: </strong>We developed an oHSV that expresses IL-27 (C027). The antiglioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed in vivo cell-specific depletion and IL-27 blockade alongside in vitro T cell stimulation assays. Local and systemic antitumor memory was evaluated by both orthotopic and flank tumor rechallenge of C027-treated long-term survivors.</p><p><strong>Results: </strong>C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector CTLs and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit in vivo and IL-27 enhanced CTL function in vitro. C027-treated mice that survived their initial tumors had local and systemic antiglioma memory rejecting tumors on rechallenge.</p><p><strong>Conclusions: </strong>Our findings demonstrate that IL-27 expression by oHSV significantly improves antiglioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for MGs.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232459/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583912","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":"Correction: Novel fusion superkine, <i>IL-24S/IL-15</i>, enhances immunotherapy of brain cancer.","authors":"","doi":"10.1136/jitc-2024-011198corr1","DOIUrl":"10.1136/jitc-2024-011198corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583911","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":"Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis.","authors":"Ruixuan Liu, Qi Liu, Yuming Wang, Tianyi Liu, Zhusheng Zhang, Chong Zhao, Haipeng Tao, Elizabeth Ogando-Rivas, Paul Castillo, Weibin Zhang","doi":"10.1136/jitc-2025-012269","DOIUrl":"10.1136/jitc-2025-012269","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma (OS) with pulmonary metastasis remains challenging due to limited treatment options and the immunosuppressive nature of the tumor microenvironment (TME). Bacteria-mediated cancer therapy has emerged as a promising strategy for solid tumors but often suffers from limited efficacy due to the immunosuppressive TME, which restricts the intensity and durability of the antitumor immune response. To overcome these challenges, we engineered a novel Salmonella strain, VNP20009-CCL2-CXCL9 (VNP-C-C), leveraging the intrinsic tumor tropism of <i>Salmonella typhimurium</i> VNP20009 (VNP) and improving immune modulation through the recruitment of effector immune cells into the TME by the chemokines CCL2 and CXCL9.</p><p><strong>Methods: </strong>VNP-C-C was genetically engineered through electroporation of Plac-CCL2-CXCL9 plasmid and validated in vitro. Its antitumor efficacy, immune regulation capacity and immunomodulatory mechanisms were evaluated in vitro by using OS cell lines and immune cells (dendritic cells (DCs) and macrophages (Mφs)) and in vivo by using both immunocompromised and immunocompetent mouse models of OS lung metastasis.</p><p><strong>Results: </strong>VNP-C-C effectively accumulated within tumors, triggering immunogenic cell death and subsequently activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, thereby robustly promoting type I interferon secretion. The chemokines CCL2 and CXCL9 amplified the immune response by recruiting DCs, Mφs, and T cells to the TME. This orchestrated immune modulation reprogrammed tumor-associated macrophages to an antitumor phenotype, induced DCs maturation, significantly increased T-cell infiltration and activation within tumors, and promoted systemic T-cell memory formation in peripheral lymphoid organs. These effects collectively inhibited OS lung metastasis progression and provided survival benefits in mouse models.</p><p><strong>Conclusion: </strong>The engineered bacterial strain VNP-C-C effectively converts the OS lung metastatic TME into a pro-inflammatory milieu, thereby stimulating robust innate and adaptive immune responses. This offers a highly promising therapeutic avenue for OS lung metastasis with considerable translational potential in cancer immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12215138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540279","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}