Journal for Immunotherapy of Cancer最新文献

{"title":"Antagonism of estrogen-related receptor-α inhibits mitochondrial oxidative phosphorylation and reduces M2 macrophage infiltration in endometrial cancer.","authors":"Jincheng Ma, Xiaodan Mao, Yuan Ren, Xite Lin, Qibin Wu, Maotong Zhang, Jingxuan Ye, Shuxia Xu, Pingping Su, Gang Chen, Chaoyang Sun, Alexander Mustea, Pengming Sun","doi":"10.1136/jitc-2025-012521","DOIUrl":"10.1136/jitc-2025-012521","url":null,"abstract":"<p><strong>Objective: </strong>Endometrial cancer (EC) is a female malignancy closely linked to metabolic dysregulation. Most patients with EC exhibit poor responses to immunotherapy, underscoring the need to identify novel therapeutic targets at the intersection of metabolism and immune regulation.</p><p><strong>Methods: </strong>In vitro: integrated proteomics, CUT&Tag (cleavage under targets and tag mentation) sequencing, dual-luciferase reporter assays, lipidomic profiling, and macrophage-tumor co-culture systems collectively demonstrated estrogen-related receptor (ERR) α's dual metabolic-immunomodulatory role in KLE and HEC-1A human cell lines. Patient-derived organoids were used to validate the therapeutic efficacy of ERRα targeting. In vivo, the KLE cell xenograft model was used to evaluate tumorigenicity and therapeutic efficacy in mice. In humans, a retrospective cohort of 166 patients with EC was analyzed by immunohistochemistry (IHC) to quantify ERRα expression and macrophage infiltration, establishing clinical correlations and therapeutic implications. Spatial analysis of M2 macrophages in EC progression was performed using multiplex IHC.</p><p><strong>Results: </strong>In EC cells, ERRα transcriptionally upregulates protein tyrosine phosphatase mitochondrial 1 through direct promoter binding (-624 to -609 bp). This interaction promotes cardiolipin biosynthesis, thereby stabilizing mitochondrial inner membrane ultrastructure, enhancing oxidative phosphorylation activity, and elevating reactive oxygen species (ROS) levels. Subsequently, ROS activates the NF-κB signaling axis, inducing CCL2 secretion to recruit M2 macrophages into the tumor microenvironment. Importantly, combined inhibition of ERRα (using XCT790) and CCL2 (using carlumab) significantly enhanced antitumor efficacy in EC. Additionally, ERRα expression in EC tissues may serve as a clinical indicator for disease evaluation.</p><p><strong>Conclusions: </strong>This study uncovers a pivotal role of the ERRα metabolic axis in reshaping the EC immune microenvironment, providing the mechanistic evidence linking mitochondrial lipid metabolism to macrophage-driven immunosuppression. Our findings establish a theoretical foundation for developing combination therapies targeting metabolic-immune crosstalk, offering a strategy to overcome immunotherapy resistance in EC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145191484","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":"Addition of oncolytic virotherapy to clinical isolated limb perfusion for melanoma and sarcoma activates antitumor immunity.","authors":"Andrew J Hayes, Emma J Davies, Michelle Wilkinson, Henry G Smith, Pablo Nenclares, Tom Lund, Adrian Larkeryd, Elizabeth Appleton, Emmanuel Christian Patin, Malin Pedersen, Antonio Rullan, Hesham S Mohamed, Lauren Aronson, Jessica Murphy, Lorna Grove, David Mansfield, Martin Mclaughlin, Kevin J Harrington, Alan Melcher","doi":"10.1136/jitc-2025-012446","DOIUrl":"10.1136/jitc-2025-012446","url":null,"abstract":"<p><strong>Background: </strong>We previously showed that oncolytic virotherapy delivered by isolated limb perfusion (ILP), combined with immune checkpoint inhibition, prevents both local tumor progression and systemic metastases in an animal sarcoma model.</p><p><strong>Methods: </strong>We describe a first-in-human phase I/II trial combining oncolytic herpes simplex virus, talimogene laherparepvec (T-VEC), with melphalan and tumor necrosis factor-alpha delivered by ILP, in patients with locally advanced sarcoma or melanoma.</p><p><strong>Results: </strong>T-VEC/ILP is well tolerated, with an overall response rate of 53% in all patients and 44% in sarcoma. Importantly, we report durable complete responses in sarcoma subtypes usually unresponsive to ILP. Translational analysis of longitudinal tumor and blood samples showed that T-VEC induced an inflammatory gene expression profile within injected tumors, which was more sustained in sarcoma than in melanoma. In relation to clinical outcome, responding patients with sarcoma showed a greater increase in gene expression for interferon response after virus treatment than non-responding patients. Analysis of the T-cell repertoire (TCR) in tumor and blood showed that clonality was higher in the tumor, but lower in the blood, in responders following virotherapy, suggesting that virus treatment may expand intratumoral T-cell clones that recognize tumor and/or viral antigens. Increased TCR diversity in the blood was suggestive of a systemic immune response.</p><p><strong>Conclusions: </strong>These clinical and translational findings support the further development of oncolytic virotherapy/ILP combinations to activate both systemic and local antitumor immunity, including in tumor types such as sarcoma, which are largely refractory to current treatment with immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481388/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145175609","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":"Targeting SQLE-mediated cholesterol metabolism to enhance CD8⁺ T cell activation and immunotherapy efficacy in hepatocellular carcinoma.","authors":"Shuang Qiao, Hao Zou, Yulan Weng, Yi-Fan Liu, Weihao Li, Xing-Juan Yu, Lian Li, Limin Zheng, Jing Xu","doi":"10.1136/jitc-2025-012345","DOIUrl":"10.1136/jitc-2025-012345","url":null,"abstract":"<p><strong>Background: </strong>The sustained effectiveness of anti-programmed cell death protein-1 (PD1) treatment is limited to a subgroup of patients with hepatocellular carcinoma (HCC) due to the tumor microenvironment heterogeneity, highlighting the need to identify targetable biomarkers that synergize with PD1 blockade. Abnormal cholesterol metabolism plays a critical role in HCC progression, along with growing evidence indicating its complex immunomodulatory effects within the tumor microenvironment. However, the interplay between cholesterol homeostasis and immune evasion remains elusive.</p><p><strong>Methods: </strong>Transcriptomic and clinical data from HCC datasets were analyzed to identify cholesterol metabolism-related targets. Multiplex immunostaining and flow cytometry were applied to examine the immune landscape association with squalene epoxidase (SQLE) in human and murine tumors. Mechanistic studies were conducted in vitro, and co-culture experiments of tumor cells and T cells were followed by metabolomics and transcriptome analyses. Therapeutic efficacy was evaluated in mouse HCC models.</p><p><strong>Results: </strong>We demonstrated that elevated SQLE expression in human HCC was associated with poor clinical outcomes and correlated with reduced CD8⁺ T cell infiltration and activation. Pharmacological inhibition or genetic knockdown of SQLE in tumor cells promoted CD8⁺ T cell proliferation and activation in co-culture experiments. Untargeted metabolomics identified 27-hydrocholesterol, an oxysterol derived from tumor cells, as a key factor impairing CD8⁺ T cell function via cholesterol dysregulation. SQLE inhibition in tumor cells suppressed oxysterols secretion, therefore overcoming cholesterol restrictions and enhancing the immune responses of CD8⁺ T cells. Moreover, SQLE targeting with terbinafine restored antitumor immunity and synergized with anti-PD1 therapy in HCC.</p><p><strong>Conclusion: </strong>Targeting tumorous SQLE restores CD8⁺ T cell function by overcoming cholesterol restrictions via oxysterol-SREBP2 signaling, highlighting SQLE as a potential therapeutic target to enhance immunotherapy efficacy in HCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145175644","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":"High Treg and PMN-MDSC densities are a hallmark of tertiary lymphoid structures in fatal cases of cervical cancer.","authors":"Linn A Syding, Klára Plačková, Lucie Pavelková, Cecilia Aquino-Perez, Saskia J Santegoets, Jan Laco, Marek Grega, Pavel Dundr, Kristýna Němejcová, Miroslav Hodek, Jan Bouček, Michal Zábrodský, Hana Vošmiková, Michael J Halaška, Lukáš Rob, Petr Čelakovský, Viktor Chrobok, Munachiso Ndukwe Iheme, Ivan Práznovec, Milan Vošmik, Stanislav Katina, David Cibula, Aleš Ryška, Sjoerd H van der Burg, Radek Špíšek, Anna Fialová","doi":"10.1136/jitc-2025-012613","DOIUrl":"10.1136/jitc-2025-012613","url":null,"abstract":"<p><strong>Background: </strong>High densities of tertiary lymphoid structures (TLSs) are associated with improved clinical outcomes in various malignancies, including human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). However, the role of TLSs in shaping antitumor immunity in HPV-induced cervical cancer (CESC) remains unclear. Therefore, we analyzed the density, composition, and prognostic impact of TLSs in patients with CESC as well as patients with HNSCC.</p><p><strong>Methods: </strong>Multiplex immunofluorescence, immunohistochemistry, and spatial transcriptomics were used to analyze TLS density and composition in HNSCC and CESC tissue sections with respect to patient prognosis. The spatial approach was supplemented by flow cytometry-based analysis of the polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) phenotype in freshly resected primary tumor tissues.</p><p><strong>Results: </strong>Although both indications were associated with HPV infection, we confirmed a positive correlation between TLS density and improved overall survival only in patients with HNSCC. The TLS composition differed markedly between HNSCC and CESC samples, with a shift toward high regulatory T cell (Treg) and PMN-MDSC abundance in CESC samples. The highest Treg and PMN-MDSC levels were observed in patients with CESC who died of the disease. CESC-infiltrating PMN-MDSCs showed high arginase 1 expression, which correlated with diminished T-cell receptor (TCR)ζ chain expression in CESC-infiltrating T cells. Additionally, the high number of PMN-MDSCs in TLSs was associated with the absence of HPV-specific T cells in CESC.</p><p><strong>Conclusions: </strong>Unlike in HNSCC, the composition of TLSs, rather than their quantity, was associated with the overall survival of patients with CESC. High numbers of Tregs and PMN-MDSCs infiltrating immature TLSs prevail in patients with CESC who succumbed to the disease and seem to affect tumor-specific immune responses.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149149","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":"Novel oncolytic adenovirus-based PEPvIII vaccine displays a super antitumor effect in glioma models.","authors":"Yuankun Chen, Lingyue Ren, Xia Li, Yufan Wu, Hongjuan Zhao, Ruru Feng, Weifeng Zhang, Junli Zhao, Peiyan Yang, Qinwen Mao, Haibin Xia","doi":"10.1136/jitc-2024-010750","DOIUrl":"10.1136/jitc-2024-010750","url":null,"abstract":"<p><strong>Background: </strong>Currently, an epidermal growth factor receptor variant III (EGFRvIII)-specific peptide (PEPvIII) vaccine has not achieved satisfactory outcomes in several clinical trials for glioblastoma. This is probably due to the poor immunogenicity of the PEPvIII peptide vaccine and the harshly immunosuppressive tumor microenvironment. Hence, identifying strategies to enhance tumor-specific T cell immune responses and reverse immune suppression is crucial for achieving the maximum beneficial therapeutic effect.</p><p><strong>Methods: </strong>To enhance the immunogenicity of the PEPvIII vaccine, we have developed a novel oncolytic adenovirus-based vaccine by genetically incorporating the PEPvIII peptide into the adenovirus hexon protein, naming this construct Ad5-D24-PEPvIII. However, the upregulation of programmed cell death-ligand 1 (PD-L1) expression in the tumor microenvironment following oncolytic virus therapy may limit its therapeutic effectiveness. To address this, we first attempted to co-express soluble programmed cell death 1 (sPD-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the E4 region of Ad5-D24-PEPvIII. Subsequently, we combined the oncolytic adenovirus-based PEPvIII vaccine carrying GM-CSF with a PD-L1 inhibitor. Two immunocompetent mouse glioma models were used to evaluate their antitumor effects in vivo. The immune cell status within the tumor microenvironment was assessed using flow cytometry and immunohistochemistry. CD8⁺ T cell immune responses were evaluated by ELISA.</p><p><strong>Results: </strong>Local administration of Ad5-D24-PEPvIII, which presents high copies of tumor-specific antigen PEPvIII in the hexon protein, successfully activated PEPvIII-specific T cell responses. Co-expression of sPD-1 and GM-CSF in the E4 region of Ad5-D24-PEPvIII could increase the release of proinflammatory cytokines, activate myeloid cells and promote the maturation of dendritic cells, thereby further enhancing the activation and proliferation of CD8⁺ T cells targeting tumor antigens. More importantly, when the oncolytic adenovirus-based PEPvIII vaccine carrying GM-CSF was combined with a PD-L1 inhibitor, it could also broaden the tumor antigenic epitopes and significantly inhibit tumor growth in immunocompetent glioma mouse models.</p><p><strong>Conclusion: </strong>Our work suggests that the efficient presentation of PEPvIII, achieved by modifying the hexon protein of the oncolytic adenovirus, combined with the adjuvant function of GM-CSF and blockade of the PD-1/PD-L1 axis, significantly enhances the therapeutic efficacy of the PEPvIII vaccine against glioblastoma. In addition, this combination strategy also provides a promising and personalized treatment for patients with cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145149228","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 inhibition of USP7 promotes antitumor immune responses.","authors":"Angelika Muchowicz, Katarzyna M Głuchowska, Marcin M Grzybowski, Małgorzata Szostakowska-Rodzos, Tomasz Rejczak, Agnieszka Belczyk-Ciesielska, Mieszko M Wilk, Agnieszka Kikulska, Patrycja Marzeta-Assas, Agnieszka Zagozdzon, Paulina Pomper, Katarzyna Piwowar, Marta Bryla, Alicja Wojciechowska, Jacek Chrzanowski, Julita Nowicka, Anna Gzik, Lukasz Joachimiak, Robert Koralewski, Roman Błaszczyk, Radoslaw Zagozdzon, Zbigniew Zasłona","doi":"10.1136/jitc-2025-012287","DOIUrl":"10.1136/jitc-2025-012287","url":null,"abstract":"<p><strong>Background: </strong>Ubiquitin-specific peptidase 7 (USP7) is a deubiquitinating enzyme that removes ubiquitin from specific protein substrates to modify their degradation rates thereby regulating crucial cellular processes integral to cancer. Conspicuously, overexpression of USP7 is strongly associated with the progression and poor prognosis in various cancers. Therefore, the design of potent and selective USP7 inhibitors poses an attractive therapeutic approach. The mechanism of action of USP7 inhibitors in cancer cells relies on MDM2 depletion and the restoration of p53.</p><p><strong>Methods: </strong>In this study, we present OAT-4828, a novel and highly potent USP7-selective lead compound with a pharmacokinetic profile suitable for an oral administration. In in vivo models of melanoma and colon cancers, we determine the antitumor activity of OAT-4828, revealing its significant influence on various immune cell populations by flow cytometry.</p><p><strong>Results: </strong>We provide evidence that OAT-4828 alters the tumor microenvironment, affecting immune cells including T cells, macrophages, and dendritic cells. As a result, OAT-4828 enhances antitumor functions, specifically improves T-cell activity, manifested by increased cytotoxicity, which is crucial for the effectiveness of OAT-4828 in vivo. Moreover, OAT-4828 changes the phenotype of macrophages and dendritic cells by decreasing the level of immunosuppressive proteins, such as programmed death-ligand 1. Translational results from the human co-culture system revealed the unexpected anti-angiogenic effect of the USP7 inhibitor, which was not observed when compared with an MDM2 inhibitor.</p><p><strong>Conclusions: </strong>Overall, OAT-4828 demonstrates significant anticancer efficacy in melanoma and colon cancer models by activating the immune system, suggesting that USP7 may function as a checkpoint contributing to immunosuppression in cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145148713","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":"Second signals for cancer immunotherapy.","authors":"Scott H Olejniczak, Michael T Lotze, Dimitris Skokos","doi":"10.1136/jitc-2024-010530","DOIUrl":"10.1136/jitc-2024-010530","url":null,"abstract":"<p><p>Recent years have seen renewed appreciation of the critical role played by the prototypic T cell co-stimulatory receptor CD28 in cancer immunotherapy. Inhibition of co-stimulation by direct competition, as exemplified by cytotoxic T-lymphocyte associated protein 4 (CTLA-4) competition with CD28 for B7 ligands, or interference with intracellular signaling, such as that mediated by SHP2 phosphatase recruited to programmed cell death protein-1 (PD-1), provides tumors with a means to avoid elimination by cytotoxic T cells. Reversing this inhibition or providing co-stimulation by alternative means-bispecific antibodies, chimeric antigen receptors, etc-is the mechanistic basis behind the success of many modern cancer immunotherapies. As such, understanding the complexities of T cell co-stimulation and the various receptors driving it has taken on new importance. In this commentary, we highlight recent studies in this space and discuss their contributions to our understanding of T cell co-stimulatory receptors in cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137734","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":"Immune-related adverse events occurring rapidly after a single dose of immune checkpoint blockade.","authors":"Romain Guitton, Ariane Laparra, Noemie Chanson, Stephane Champiat, Francois-Xavier Danlos, Jean-Marie Michot, Sabine Messayke, Aurelien Marabelle, Olivier Lambotte","doi":"10.1136/jitc-2025-012756","DOIUrl":"10.1136/jitc-2025-012756","url":null,"abstract":"<p><strong>Background: </strong>The optimal dosing regimen for immune checkpoint blockade (ICB) remains a critical question in oncology. Although immune-related adverse events (irAEs) are common with ICB, the incidence and severity of irAEs following a single dose of anti-programmed death-ligand 1 (PD-(L)1) blockade have not yet been investigated.</p><p><strong>Methods: </strong>We conducted a single-center prospective cohort study at Gustave Roussy (Villejuif, France), based on a population of patients with advanced or metastatic cancer, using data from the French Registre des Effets Indésirables Sévères des Anticorps Monoclonaux (REISAMIC) registry, a pharmacovigilance database dedicated to irAEs. Between December 2014 and December 2023, we included adults with solid or hematologic malignancies who presented with irAEs after the first infusion of anti-PD-(L)1 therapy, regardless of the treatment indication, and before the administration of the second dose of ICB. The main outcomes included the incidence and characteristics of irAEs, particularly severe (grade 3-4) and fatal (grade 5) events.</p><p><strong>Results: </strong>Of the 3565 patients prospectively followed in REISAMIC, 70 (1.96%) experienced irAEs following a single infusion. Of these 70 patients, severe irAEs (grade 3-4) occurred in 20 patients (37.1%), and fatal irAEs (grade 5) were recorded in three cases (4.3%), indicating significant toxicity risks. The most frequently affected organ systems were the skin (14 (20%)), musculoskeletal system (11 (15.7%)), endocrine system (9 (12.9%)), and cardiovascular system (9 (12.9%)). Most irAEs developed within 20 days after treatment, with a median onset time of 14 days (IQR, 5-21). Multiorgan toxicities were observed in 10% of patients. Despite the severity, no predictive markers for fatality, multiorgan involvement, or early onset were identified, including pre-existing autoimmune conditions.</p><p><strong>Conclusions: </strong>This study underscores the notable risk of severe and fatal irAEs following a single dose of anti-PD-(L)1 therapy in patients with advanced/metastatic cancer. The absence of predictive markers for fatality, multiorgan toxicities, or early onset highlights the need for enhanced patient monitoring during the initial treatment phase. Further research is needed to optimize dosing regimens, balancing safety and efficacy for safer clinical use of immune checkpoint blockade.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137752","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":"Tertiary lymphoid structures in Merkel cell carcinoma facilitate naïve and central memory T-cell infiltration linked to immunotherapy response.","authors":"Nalini Srinivas, Ivelina Spassova, Kuan Cheok Lei, Jiwei Gao, María José Pino, Giovanni Giglio, Simo Kitanovski, Mazdak Dalkoohi, Elisabeth Livingstone, Ulrike Leiter, Peter Mohr, Thilo Gambichler, Ingo Stoffels, Selma Ugurel, Phyllis Fung-Yi Cheung, Camilla Engblom, Weng-Onn Lui, Jürgen Christian Becker","doi":"10.1136/jitc-2025-012224","DOIUrl":"10.1136/jitc-2025-012224","url":null,"abstract":"<p><strong>Background: </strong>The presence of tertiary lymphoid structures (TLS) in solid tumors, including Merkel cell carcinoma (MCC), is associated with a better prognosis and a better response to immunotherapy with immune checkpoint inhibition (ICI). The detailed mechanisms by which TLS influence antitumor immune responses are only partially understood.</p><p><strong>Methods: </strong>Clinically annotated tumor tissues of 27 patients with MCC were obtained prior to ICI therapy. Tumor samples were subjected to transcriptomic and multiplex immuno-visual profiling, T-cell receptor (TCR) clonotype mapping, as well as-in selected cases-spatial transcriptomics to comprehensively characterize the tumor immune microenvironment.</p><p><strong>Results: </strong>Weighted gene co-expression network analysis (WGCNA) of transcriptomic data in combination with topological overlap measures indicated a higher abundance of TLS in tumors of patients with MCC responding to ICI therapy. This concept was substantiated through immunomorphological analyses, revealing mature B-cell follicle-like structures characterized by high endothelial venules (HEVs). Further supporting HEVs as critical entry points for naïve T cells, the presence of TLS was correlated with a pronounced infiltration of CD4⁺ and CD8⁺ T cells, exhibiting both naïve and central memory phenotypes. The TCR repertoire of these infiltrates exhibited enhanced richness and diversity with a pronounced reactivity toward Merkel cell polyomavirus-derived T-cell epitopes. Spatially resolved RNA and V(D)J sequencing revealed the expression of genes associated with T-cell recruitment within TLS, alongside the presence of naïve and central memory T-cell markers. Notably, individual clonally expanded TCR transcripts were detected both within TLS and among tumor-infiltrating lymphocytes. The latter were associated with low expression of memory cell markers and high expression of effector cell markers. Additionally, a spatial gradient in the expression of genes linked to immune stress in MCC cells-such as those involved in the interferon-γ response and antigen processing and presentation machinery-originated in proximity to the TLS.</p><p><strong>Conclusion: </strong>Our findings are consistent with a key role of TLS in shaping immune interactions within the MCC microenvironment, driving the recruitment of diverse tumor-reactive T cells. These insights hold promise for advancing immunotherapeutic strategies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137712","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":"Infliximab is a safe and effective treatment in steroid-refractory immune-related hepatitis.","authors":"Kim Nikola Oliva, Lisa Arnold, Lucie Heinzerling, Friedegund Meier, Sören Hartmann, Katharina Meier, Julia Huynh, Max Schlaak, Anja Gesierich, Iris Dirven, Jörg Trojan, Johannes Kleemann, Bastian Schilling","doi":"10.1136/jitc-2025-013038","DOIUrl":"10.1136/jitc-2025-013038","url":null,"abstract":"<p><strong>Background: </strong>The incidence of severe immune-related hepatitis (irHepatitis) Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 under combination therapy with ipilimumab and nivolumab ranges from 15% to 20%. Current clinical guidelines recommend initiating treatment with systemic corticosteroids, followed by second-line immunosuppressants such as mycophenolate mofetil. In contrast, the use of the tumor necrosis factor-α antibody infliximab-commonly administered for other immune-related adverse events such as colitis-is generally not recommended for irHepatitis. A recent single-center study, however, reported the use of infliximab for steroid-refractory irHepatitis in 10 patients without signs of infliximab-associated hepatotoxicity and overall favorable efficacy.This multicenter retrospective analysis aimed to evaluate the safety and efficacy of infliximab in patients with steroid-refractory irHepatitis.</p><p><strong>Methods: </strong>A total of 28 patients with advanced cutaneous melanoma and irHepatitis during immune checkpoint inhibitor (ICI) therapy were included from five university hospitals in Germany and one in Belgium. Of these, 27 patients were in American Joint Committee on Cancer stage IV (8th edition).</p><p><strong>Results: </strong>All patients received ipilimumab plus nivolumab. The Eastern Cooperative Oncology Group performance status was 0 in 75.0% of patients, and nearly all (27/28) developed severe irHepatitis of CTCAE grade 3 or 4 (V.5.0). The median time to onset of irHepatitis was 46 days after first ICI administration. 96.4% of patients were initially treated with systemic corticosteroids. The median interval between onset of irHepatitis and the first dose of infliximab was 23 days. Infliximab was administered intravenously at a dose of 5 mg/kg. 22 patients received one dose, while 6 patients received two doses. In 82.1% of patients, corticosteroids were tapered to less than 5 mg prednisolone equivalent within a median period of 75 days. Clinical remission for irHepatitis (≤CTCAE grade 1) was achieved in 92.9% of patients and was reached after a median time of 21 days following the first infliximab administration. During a median follow-up of 349 days, no deaths or drug-induced liver injury attributable to infliximab were observed.</p><p><strong>Conclusion: </strong>In this retrospective analysis, infliximab appeared to be effective and safe for the treatment of steroid-refractory irHepatitis, with no evidence of hepatotoxicity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 9","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12458706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137701","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}