Journal for Immunotherapy of Cancer最新文献

{"title":"Stromal cells modulate innate immune cell phenotype and function in colorectal cancer via the Sialic acid/Siglec axis.","authors":"Aoise O'Neill, Norashikin Zakaria, Courtney Bull, Hannah Egan, Shania M Corry, Niamh A Leonard, Clodagh O'Meara, Linda Howard, Anastasija Walsh, Eileen Reidy, Jenny Che, Li Peng, Lizhi Cao, Laurence J Egan, Thomas Ritter, Margaret Sheehan, Aoife Canney, Kevin Culligan, Aisling M Hogan, Sean O Hynes, Philip D Dunne, Michael O'Dwyer, Oliver Treacy, Aideen E Ryan","doi":"10.1136/jitc-2025-012491","DOIUrl":"https://doi.org/10.1136/jitc-2025-012491","url":null,"abstract":"<p><strong>Background: </strong>The immunosuppressive tumor microenvironment reduces immune response effectiveness in stromal-rich tumors, including consensus molecular subtype 4 colorectal cancer (CRC). Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote cancer progression by suppressing anti-tumor immune responses. Hypersialylation of glycans on tumors engages Siglec receptors on immune cells, driving immune dysfunction, but its role in stromal-mediated suppression of innate immunity remains unclear.</p><p><strong>Methods: </strong>Sialylation, Sialic acids and Siglec ligands were measured on CRC tissue, primary human normal-associated fibroblasts (NAFs), CAFs, and tumor-conditioned MSCs (MSC<sup>TCS</sup>) using transcriptional profiles, immunohistochemistry and flow cytometry, respectively. The effect of stromal cell sialylation on macrophages and NK cells was assessed in <i>ex vivo</i> human primary stromal and immune cell co-cultures, and expression of Siglec-10 and immune cell phenotype markers and function was measured by flow cytometry and real-time imaging. Using an immunocompetent Balb/c CT26 mouse model, we induced tumors with/without conditioned stromal cells, with/without pretreatment of stromal cells with sialyltransferase inhibitor (3FAX) or sialidase (E610). We assessed the effect of stromal cell sialylation on macrophages and NK cells in the tumor and secondary lymphoid tissues by flow cytometry.</p><p><strong>Results: </strong>Stromal cells, including CAFs, in CRC tumors are highly sialylated compared with epithelial cancer cells and are associated with high expression of the sialyltransferase <i>ST6GALNAC6</i>. Genetic knockdown of <i>ST6GALNAC6</i> reduced the expression of stromal cell Siglec-10 ligands in MSCs. CAFs and MSC<sup>TCS</sup> induced Siglec-10 on macrophages and NK cells and impaired macrophage phagocytosis and NK cell cytotoxicity. Sialidase treatment reduced Siglec-10 expression, restoring macrophage and NK cell antitumor functions. <i>In vivo</i> and <i>ex vivo</i>, desialylation of stromal cells increased macrophage activation (CD11b<sup>+</sup>CD80<sup>+</sup>) and reduced immunosuppressive marker expression (CD206, PD-L1, Siglec-G) in lymphoid tissues, indicating sustained systemic anti-tumor immunity. Intratumoral NK cells exhibited high Siglec-G expression and impaired cytotoxicity, and granzyme B expression significantly increased with sialidase treatment of stromal cells. In an inflammatory tumor model, inflammatory tumor-conditioned MSCs (MSC<sup>iTCS</sup>) promoted metastasis and Siglec-G induction on NK cells and macrophages, both reversed by sialyltransferase inhibition, underscoring the effects of stromal modulation of innate immune cell function in inflammatory tumors.</p><p><strong>Conclusions: </strong>Stromal cell sialylation modulates innate immune suppression in CRC via the sialic acid/Siglec axis. Targeting stromal sialylation restores NK cytotoxic","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329198","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":"EP300 compromises antitumor immunity by increasing SOCS1 expression.","authors":"Yanqiong Zeng, Ying Zhou, Jiayin Ruan, Wancheng Liu, Huimin Fan, Na Liu, Lili Li, Jiayuan Ma, Xiaoxia Jin, Lihua Duan, Youguo Chen, Genhong Cheng, Heng Yang","doi":"10.1136/jitc-2025-011488","DOIUrl":"10.1136/jitc-2025-011488","url":null,"abstract":"<p><strong>Background: </strong>Beyond supporting cancer cell proliferation, tumor growth relies on the ability of cancer cells to evade immune surveillance. Identifying novel molecules that promote tumor immune escape may help develop more effective immunotherapeutic strategies. The histone acetyltransferase E1A-binding protein p300 (EP300) is a key epigenetic regulator that modulates gene transcription through chromatin remodeling and acetylation of histones and transcription factors. However, its role in regulating immune evasion remains incompletely understood. This study investigates the impact of EP300 on tumor immune escape and suggests its potential as an immunotherapeutic target.</p><p><strong>Methods: </strong>We analyzed tissue microarrays from patients with lung adenocarcinoma using immunohistochemistry to compare EP300 expression between cancerous tissues and benign tissues. <i>Ep300</i>-knockout cancer cells were generated using CRISPR-Cas9. Animal models were employed to assess the effect of <i>Ep300</i> depletion on tumor progression and intratumoral CD8⁺ T cell infiltration. RNA sequencing, chromatin immunoprecipitation sequencing, flow cytometry, and western blot were used to explore the mechanism by which EP300 regulates antigen-presenting gene expression.</p><p><strong>Results: </strong>EP300 was significantly upregulated in cancerous tissues compared with benign tissues. Genetic ablation of <i>Ep300</i> in cancer cells markedly suppressed tumor growth <i>in vivo</i> and enhanced CD8⁺ T-cell infiltration. Mechanistically, EP300 upregulates suppressor of cytokine signaling 1 (SOCS1) expression, thereby inhibiting signal transducer and activator of transcription 1 phosphorylation. This leads to downregulation of antigen-presenting genes, enabling cancer cells to evade immune surveillance by CD8⁺ T cells.</p><p><strong>Conclusions: </strong>EP300 facilitates tumor immune evasion by suppressing antigen-presenting gene expression via SOCS1 upregulation. Our findings reveal a novel role for EP300 in mediating immune escape and propose a potential therapeutic strategy to enhance antitumor immunity.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12530425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145300697","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":"Consensus-based disease definitions for endocrine immune-related adverse events of immune checkpoint inhibitors.","authors":"Ling Zhu, Yee-Ming M Cheung, Cherie Chiang, Emily J Gallagher, Ole-Petter R Hamnvik, Jennifer Mammen, Zoe Quandt, Renisha Jones, Jon McDunn, Huda Al-Bahadili, Trevor Angell, Irina Bancos, Allison Betof Warner, Susan Blackwell, Cassandra Calabrese, Tracey A Cho, Michael Dougan, Michelle Ferreira, Pauline Funchain, Justine Herndon, Douglas B Johnson, Randol Kennedy, Meenal Kheterpal, Michel Khouri, Melissa G Lechner, Annette M Lim, Alina Markova, Alexa Meara, Laura Overton, Ana Luisa Perdigoto, Nirupa Sachithanandan, Elad Sharon, Lavinia Spain, Katy Tsai, Mark Yarchoan, Kerry L Reynolds, Afreen Shariff","doi":"10.1136/jitc-2025-011865","DOIUrl":"10.1136/jitc-2025-011865","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs.A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves' disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories-\"thyroid\", \"pituitary and adrenal\", and \"diabetes mellitus\". A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements.Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12530408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145300749","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":"Macrophages expressing chimeric cytokine receptors have an inflammatory phenotype and antitumoral activity upon IL-10 or TGFβ stimulation.","authors":"Sabrina Traxel, Florian Schmidt, Corina Beerli, Dinh-Van Vuong, Roberto F Speck, Simon Bredl","doi":"10.1136/jitc-2024-011057","DOIUrl":"10.1136/jitc-2024-011057","url":null,"abstract":"<p><strong>Background: </strong>Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks hormone receptors and human epidermal growth factor receptor 2 (HER2) amplification, making it unresponsive to standard hormone or HER2-targeted therapies. Although immune checkpoint inhibitors (ICIs) have shown promise in tumors with high lymphocyte infiltration, their efficacy remains limited in tumors with minimal lymphocyte infiltration. Inflammatory macrophages are associated with better prognosis and response to ICIs. The tumor microenvironment (TME), however, is rich in interleukin (IL)-10 and transforming growth factor β (TGF β) inducing immunosuppressive, protumoral macrophages. Therefore, we engineer macrophages with a chimeric cytokine receptor (ChCR), designed to bind IL-10 or TGFβ and promote the generation of inflammatory and antitumoral active macrophages. Such genetically modified macrophages could be used as adoptive cell therapy (ACT).</p><p><strong>Methods: </strong>The ChCRs consist of the extracellular domains of the IL-10 or TGFβ receptor fused to the intracellular domains of interferon (IFN)-γ receptor. Upon binding IL-10 or TGFβ, the ChCRs shall trigger STAT1 signaling, eventually rendering the macrophages pro-inflammatory. We transduced human primary macrophages with a lentiviral vector expressing the ChCR and analyzed their phenotype, secretome, and transcriptome following stimulation. Moreover, we assessed their antitumoral activity in a three-dimensional (3D) co-culture assay with TNBC spheroids.</p><p><strong>Results: </strong>ChCR macrophages showed robust STAT1 activation in response to IL-10 or TGFβ stimulation, resulting in an inflammatory phenotype similar to IFN-γ-activated macrophages, as confirmed by phenotypic markers, and transcriptomic profiling. These stimulated ChCR macrophages demonstrated significant antitumoral effects in 3D TNBC spheroids. Moreover, ChCR stimulation led to the upregulation of <i>CXCL9</i> and <i>CXCL10</i>, chemokines essential for lymphocyte recruitment, and genes associated with good response to ICIs.</p><p><strong>Conclusion: </strong>We successfully engineered macrophages to express ChCRs that induce macrophages with an inflammatory phenotype and antitumoral activity within an IL-10-rich and TGFβ-rich environment. The induction of <i>CXCL9</i> and <i>CXCL10</i> expression via ChCRs stimulation could further support lymphocyte recruitment, potentially facilitating lymphocyte infiltration and disruption of the immunosuppressive TME. A future application of ChCR macrophages as an ACT might improve outcomes in patients with TNBC, particularly those with low immune cell infiltration, thereby addressing a critical unmet clinical need.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12530437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145300682","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":"Envirotune-CAR-T: a hypoxia-responsive and glutamine-enhanced CAR-T cell therapy for overcoming tumor microenvironment-mediated suppression.","authors":"Wenying Li, Jiannan Chen, Jiayi Li, Shuai Wang, Zhengliang Chen, Lianfeng Zhao, Yaoyao Zhao, Lili Gu, Jiaqi Liu, Yan Zhang, Xinhao Yang, Tianyu Chen, Zhigang Guo","doi":"10.1136/jitc-2025-012321","DOIUrl":"10.1136/jitc-2025-012321","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable success in hematologic malignancies; however, its efficacy in solid tumors remains limited. A major barrier is the immunosuppressive tumor microenvironment (TME), which is characterized by hypoxia and nutrient deprivation, leading to impaired CAR-T cell proliferation, persistence, and cytotoxic function. To address these barriers, we designed a dual-regulatory CAR-T strategy that integrates hypoxia-responsive control with metabolic enhancement to improve therapeutic efficacy in solid tumors.</p><p><strong>Methods: </strong>To overcome these barriers, we developed a next-generation CAR-T platform with dual adaptations targeting the metabolic and transcriptional constraints of the TME. Specifically, we engineered hypoxia-responsive regulatory elements derived from <i>VEGF</i> to drive sustained CAR expression under hypoxic conditions. Concurrently, we overexpressed the glutamine transporter SLC38A2 to enhance glutamine uptake and metabolic fitness in nutrient-deprived environments.</p><p><strong>Results: </strong>Compared with conventional CAR-T cells, our engineered CAR-T cells exhibited superior antitumor activity under hypoxia and nutrient stress, with enhanced proliferation, elevated memory phenotype, and reduced exhaustion markers. Mechanistically, quantitative PCR demonstrated upregulation of glutamine metabolic and glycolytic pathways, while Seahorse assays confirmed enhanced oxidative phosphorylation and glycolysis. SLC38A2 knockout reversed these enhancements, highlighting its role in sustaining CAR-T metabolic fitness.</p><p><strong>Conclusion: </strong>Our findings establish SLC38A2 as a critical metabolic regulator that enhances CAR-T antitumor efficacy, providing a promising strategy to improve the durability and efficacy of CAR-T cell therapies in TME.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286275","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":"Inhibition of osteosarcoma lung metastases by β-glucan and CD40 agonist is mediated by activation of macrophages and NK cells.","authors":"Pradeep Shrestha, Rejeena Shrestha, Eugenie S Kleinerman","doi":"10.1136/jitc-2025-012510","DOIUrl":"10.1136/jitc-2025-012510","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response.</p><p><strong>Methods: </strong>Using an experimental syngeneic OS lung metastasis BALB/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate β-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with β-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden.</p><p><strong>Results: </strong>In the pretreatment settings, mice treated with β-glucan prior to OS cell infusion developed significantly fewer lung tumor burdens and had increased survival. Pretreatment with β-glucan prevented tumor cell seeding in the lungs. In tumor-bearing mice, β-glucan treatment significantly suppressed tumor growth and prolonged overall survival. β-glucan treatment increased activated pro-inflammatory M1-like macrophages and natural killer (NK) cells secreting interferon-γ and granzyme B in the lungs. Depletion studies showed that the antitumor effect of β-glucan was dependent on macrophages and NK cells. Additionally, β-glucan treatment also induced myelopoiesis in the bone marrow. The therapeutic benefit of β-glucan was further augmented when combined with CD40a. Combination therapy significantly increased the infiltration of activated macrophages, including tumor necrosis factor-α secreting macrophages, and NK cells into the lungs compared with monotherapy. Bulk RNA sequencing of lung tissue revealed that the combination treatment group exhibited enhanced activation of antitumor innate immune pathways.</p><p><strong>Conclusions: </strong>Collectively, our findings demonstrate the antitumor activity of β-glucan against OS lung tumor burden, that combining β-glucan and CD40a increases therapeutic activity, and that this activity is mediated by activation of innate immunity (macrophages and NK cells).</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12519724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145286240","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":"Claudin 6 is a suitable target for CAR T-cell therapy in atypical teratoid/rhabdoid brain tumors and other pediatric solid tumors.","authors":"Peter J Madsen, Anna Melissa Schlitter, Carina Flemmig, Conor Dickson, Kyra Harvey, Cullen Wilson, Ezra Beaubien, Luke Patterson, Allison Stern, Crystal Griffin, Nikhil Joshi, Sreehita Hajeebu, Daniel Martinez, Phillip B Storm, Adam C Resnick, Peter Hillemanns, Martin Stanulla, Jörg Faber, Arthur Wingerter, Matthias Martin Gaida, Saskia Holtemeyer, Mark Laible, Anja Feldner, Florian Frohns, João H Duarte, Bruno Valentin Sinn, Stefan Wöll, Ugur Sahin, Özlem Türeci, Jessica B Foster","doi":"10.1136/jitc-2025-011709","DOIUrl":"10.1136/jitc-2025-011709","url":null,"abstract":"<p><strong>Background: </strong>Solid tumors comprise approximately 60% of all pediatric cancers. Relapsed or refractory tumors of the central nervous system (CNS), such as atypical teratoid/rhabdoid tumors (AT/RTs), are the leading cause of death in children with cancer. Claudin 6 (CLDN6)-specific chimeric antigen receptor (CAR) T cells have demonstrated activity in preclinical and clinical studies in various solid adult cancers. However, the suitability of CLDN6 as a target in pediatric tumors and their susceptibility to CAR T-cell therapy has yet to be established. This study aimed to evaluate the suitability of CLDN6 as a target for CAR T-cell therapy of pediatric solid tumors.</p><p><strong>Methods: </strong>Immunohistochemical CLDN6 expression was assessed in fetal normal tissues (n=91), pediatric normal tissues (n=157), and two sets of pediatric tumor tissues (n=527 and n=49) using a combined score that includes the percentage of stained cells with a 4-point intensity scale (0 to 3+). The antitumor activity of CLDN6 RNA-transduced CAR T cells against AT/RT cell lines was assessed with in vitro assays and in immunodeficient NOD-SCID-γc-/- (NSG) mouse models bearing orthotopic xenograft tumors.</p><p><strong>Results: </strong>Membranous CLDN6 expression, as detected by immunohistochemistry, was widely observed in fetal tissues but was absent in almost all non-malignant pediatric tissues, except for very rare, scattered cells with 1+ to 2+ intensity in kidney, pancreas, pituitary, and salivary gland tissues. Membranous CLDN6 expression was frequently detected in a subset of the pediatric tumor entities, including germ cell tumors (93% of samples with CLDN6-positive cells), nephroblastoma (64%), extracranial malignant rhabdoid tumors (50%), and AT/RTs (39%). In CLDN6-positive samples, CLDN6 was generally expressed with 2+ or 3+ intensity in substantial proportions of the cancer cells. Strong CLDN6 expression was also detected in single samples of hepatoblastoma, Ewing sarcoma/other embryonal tumors, and osteosarcoma.In experimental models, CLDN6-CAR T cells led to antigen-specific killing of endogenously CLDN6-expressing AT/RT cell lines in vitro and exhibited potent and specific antitumor activity in mice bearing orthotopic CLDN6-expressing AT/RT xenograft tumors.</p><p><strong>Conclusions: </strong>These results support CLDN6 as an oncofetal cell-surface antigen that may be suitable for CAR T-cell targeting in pediatric solid tumors, including those of the CNS.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516980/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274580","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":"ALCAM-CD6 axis suppression: a key determinant of immune-mediated metastasis recurrence in stage III non-small cell lung cancer.","authors":"Shaodi Wen, Xiaoyue Du, Miaolin Zhu, Chao Huang, Zeyang Lin, Ming Li, Bowen Hu, Xin Wang, Feng Jiang, Guoren Zhou, Wei Zhu, Guangchuang Yu, Cong Xu, Bo Shen","doi":"10.1136/jitc-2024-010416","DOIUrl":"10.1136/jitc-2024-010416","url":null,"abstract":"<p><strong>Background: </strong>Metastatic recurrence poses a significant challenge in cancer treatment, impacting patient survival and prognosis. Understanding the biological mechanisms behind it is essential for improving treatment strategies and patient outcomes. Lung cancer, the leading cause of cancer-related deaths, is a focus of research for treatment and prognosis. This study specifically targets stage III non-small cell lung cancer (NSCLC) patients following surgery due to their high recurrence variability.</p><p><strong>Methods: </strong>To delve into the mechanisms of metastatic recurrence in stage III NSCLC patients, we used a comprehensive experimental approach. Long-term follow-up of postoperative patients was combined with single-cell sequencing to uncover tumor microenvironment changes. In vivo and in vitro experiments, including tissue cytometry analysis, real-time PCR, western blotting, gene silencing, cell co-culture, flow cytometry, and chromatin immunoprecipitation-quantitative PCR, were conducted to investigate ALCAM-related gene regulation. Tissue samples and clinical data were collected from stage III NSCLC patients who underwent lung cancer resection between August 2018 and July 2021.</p><p><strong>Results: </strong>Analysis revealed distinct epithelial gene expression patterns between recurrence and non-recurrence groups, highlighting the reduced interaction between ALCAM ligand on epithelial cells and CD6 receptor on T cells. Lower ALCAM levels intensified an immunosuppressive state, halting cell cycle progression and promoting tumor proliferation and migration, linked to metastatic recurrence. The transcription factor MYB was identified as a key ALCAM regulator, shedding light on its impact on tumor advancement. Reduced ALCAM expression correlated with poorer prognosis, offering insights into NSCLC recurrence mechanisms.</p><p><strong>Conclusions: </strong>Our study underscores the pivotal role of the ALCAM-CD6 axis in metastatic recurrence of stage III NSCLC. ALCAM regulation not only influences immune-tumor cell interactions but also drives tumor cell proliferation and migration by affecting the cell cycle. This finding presents a promising target for NSCLC treatment and aids in assessing patient prognosis effectively.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274545","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":"Mechanistic data-informed multiscale quantitative systems pharmacology modeling framework enables the clinical translation and efficacy assessment of CAR-T therapy in solid tumors.","authors":"Siyuan Yang, Wenjie Wang, Qi Rao, Yiyang Xu, Sujie Zhang, Yuchen Qu, Qiuchuan Zhuang, Jie Mao, Laura Sun, Dong Geng, Da Xu, Chen Zhao","doi":"10.1136/jitc-2025-012331","DOIUrl":"10.1136/jitc-2025-012331","url":null,"abstract":"<p><strong>Background: </strong>Chimeric antigen receptor (CAR)-T cell therapy represents an innovative and potentially revolutionary modality in cancer treatment. Despite their great success in treating blood cancers, CAR-T therapies exhibit significantly lower effectiveness in treating solid tumors. Moreover, the preclinical-to-clinical translation of CAR-T therapies targeting solid tumors is still a challenging task because of their unique \"live cell\" nature and the substantial variability in patients' pathophysiology.</p><p><strong>Methods: </strong>We have developed a multiscale quantitative systems pharmacology (QSP) model to facilitate the clinical translation of CAR-T therapies in solid tumors. Our mechanistic modeling framework integrates the essential biological features that impact CAR-T cell fate and antitumor cytotoxicity, from cell-level CAR-antigen interaction and activation, to in vivo CAR-T biodistribution, proliferation and phenotype transition, and finally to clinical-level patient tumor heterogeneity and response variability. This modeling framework has been calibrated and validated by multimodal experimental data including published preclinical and clinical data of various CAR-T products and original preclinical data of a novel claudin18.2-targeted CAR-T product LB1908.</p><p><strong>Results: </strong>We demonstrated the general utility of this framework in facilitating clinical translation and characterizing the paired cellular kinetics-cytotoxicity response of different antigen-targeting solid tumor CAR-T cell therapies. As an example, we generated model-based virtual patients and prospectively simulated the response to claudin18.2-targeted CAR-T therapies under different dosing strategies, including step-fractionated dosing and convenient flat dose-based regimens, to inform future clinical trial implementation.</p><p><strong>Conclusions: </strong>Our translational QSP platform offers an innovative pathway to integrate multiscale knowledge and inform clinical decision-making of novel solid tumor-targeting CAR-T therapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258319","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":"Exceptional tumor-free survival of a patient with metastatic intrahepatic cholangiocarcinoma after surgery and personalized peptide vaccination: revisiting a striking case.","authors":"Ana Maia, Juliane Schuhmacher, Silvio Nadalin, Alfred Königsrainer, Karolin Thiel, Annika Nelde, Raphael S Zinser, Christopher Schroeder, Sven Mattern, Stephan Singer, Hans Bösmüller, Hans-Georg Rammensee, Markus W Löffler, Cécile Gouttefangeas","doi":"10.1136/jitc-2025-012107","DOIUrl":"https://doi.org/10.1136/jitc-2025-012107","url":null,"abstract":"<p><p>Cholangiocarcinomas are rare but aggressive liver tumors of high lethality with scarce treatment options. Here we report on the follow-up of a patient diagnosed with an intrahepatic cholangiocarcinoma who experienced repeated tumor recurrences including distant metastasis, therefore facing a dismal prognosis. At present, this patient is tumor-free for more than 8 years following repeated surgery and application of two successive personalized vaccines. In-depth functional immune cell analyses revealed a dominant CD4⁺ T-cell response against the vaccine antigens with infiltration of the tumor site and immune responses prevailing for years following the last vaccine administration. Additionally, spontaneous tumor neoantigen-specific CD4⁺ and CD8⁺ T-cell responses have been detected, which might have contributed to the outstanding outcome witnessed in this patient. This case report highlights vaccination strategies targeting non-mutated antigens as well as the increasingly recognized central role of antitumor CD4⁺ T cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 10","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145258290","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}