Journal for Immunotherapy of Cancer最新文献

{"title":"Defects in the necroptosis machinery are a cancer resistance mechanism to checkpoint inhibitor immunotherapy.","authors":"Anna Sax, Peter May, Stefan Enssle, Nardine Soliman, Tatiana Nedelko, Giada Mandracci, Fabian Stögbauer, Laura Joachim, Christof Winter, Florian Bassermann, Katja Steiger, Nadia El Khawanky, Hendrik Poeck, Simon Heidegger","doi":"10.1136/jitc-2024-010433","DOIUrl":"10.1136/jitc-2024-010433","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) of programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) reinvigorate strong polyclonal T-cell immune responses against tumor cells. For many patients, these therapies fail because the development of spontaneous immune responses is often compromised, as the tumor microenvironment (TME) lacks proinflammatory signals resulting in suboptimal activation of antigen-presenting cells (APCs). Necroptosis is a special form of programmed cell death associated with leakage of inflammatory factors that can lead to APC maturation. However, it is unclear to which extent functional necroptosis in tumor cells contributes to ICI immunotherapy.</p><p><strong>Methods: </strong>With genetically engineered tumor cell lines that lack specific components of the necroptosis machinery (mixed lineage kinase domain-like pseudokinase (MLKL), receptor interacting protein kinase 3 (RIPK3)), we addressed the importance of necroptotic tumor cell death for the efficacy of ICI immunotherapy in murine models. Preclinical data were aligned with genome-wide transcriptional programs in patient tumor samples at diagnosis and during ICI treatment for the activity of these pathways and association with treatment outcome.</p><p><strong>Results: </strong>Mice bearing MLKL-deficient or RIPK3-deficient tumors failed to control tumor growth in response to anti-PD-1/anti-CTLA-4 immunotherapy. Mechanistically, defects in the necroptosis pathway resulted in reduced tumor antigen cross-presentation by type 1 conventional dendritic cells (DCs) in tumor-draining lymph nodes, and subsequently impaired immunotherapy-induced expansion of circulating tumor antigen-specific CD8⁺ T cells and their accumulation and activation in the TME. In vitro, co-culture of tumor cells undergoing necroptotic but not apoptotic programmed cell death resulted in increased uptake by phagocytic cells, associated with maturation and activation of DCs. Treatment of tumors with the epigenetic modulator azacytidine enhanced intrinsic transcriptional activity of the necroptosis machinery, and hence their susceptibility to ICI immunotherapy. In humans, transcriptome analysis of melanoma samples revealed a strong association between high expression of <i>MLKL</i> and prolonged overall survival and durable clinical response to immunotherapy with anti-PD-1 and/or anti-CTLA-4 checkpoint inhibitors.</p><p><strong>Conclusions: </strong>Defective necroptosis signaling in tumor cells is a cancer resistance mechanism to ICI immunotherapy. Reversion of epigenetic silencing of the necroptosis pathway can render tumors susceptible to checkpoint inhibition.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143965979","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 checkpoint inhibitor-associated risk for venous thromboembolism: a comprehensive analysis.","authors":"Tamara A Sussman, Anita Giobbie-Hurder, Ian D Dryg, Michael Manos, Jason L Weirather, Nicole R LeBoeuf, F Stephen Hodi, Jean M Connors","doi":"10.1136/jitc-2024-010761","DOIUrl":"https://doi.org/10.1136/jitc-2024-010761","url":null,"abstract":"<p><strong>Background: </strong>The relationship between venous thromboembolism (VTE) and immune checkpoint inhibitor therapy (ICI) is unclear. This analysis investigates the incidence of and risk factors for VTE in VTE-naive patients with cancer receiving ICI treatment.</p><p><strong>Methods: </strong>A retrospective cohort study of patients receiving any type or combination of ICI from 2009 to 2022 at Dana-Farber Cancer Institute was conducted to identify VTE occurring after initiation of ICI treatment. Cumulative incidences of VTE were determined using Fine and Gray's methods. Associations between VTE, ICI regimens, and clinical risk factors were evaluated using propensity-score stratified, multivariable Cox proportional hazards models.</p><p><strong>Results: </strong>In 10,638 patients without a prior history of VTE, the 6-month cumulative incidence of VTE was 7.6% (95% CI: 7.1% to 8.1%) and 11.1% (95% CI: 10.5% to 11.8%) at 12 months. Clinical risk factors included: age 15-59 (HR 1.27; 95% CI: 1.12 to 1.43; p=0.002), obesity (HR: 1.41; 95% CI: 1.16 to 1.71)<u>,</u> and history of anticoagulation prior to ICI start (HR: 1.43; 95% CI: 1.26 to 1.61). Compared with pembrolizumab, treatment with ipilimumab/nivolumab increased the risk of VTE (HR: 1.36; 95% CI: 1.02 to 1.82), while durvalumab conveyed lower risk (HR: 0.52; 95% CI: 0.31 to 0.87). Treatment with programmed cell death ligand 1 had significantly reduced risk of VTE (HR: 0.79; 95% CI: 0.63 to 0.99) compared with programmed cell death 1 monotherapy. Dual ICI blockade with cytotoxic T lymphocyte antigen 4/PD-1 significantly increased the risk of VTE (HR: 1.43; 95% CI 1.12 to 1.84). Initiation of anticoagulation after starting ICI for indications other than VTE reduced the risk by 40% (HR: 0.60, 95% CI: 0.48 to 0.73).</p><p><strong>Conclusions: </strong>ICI treatment appears to be independently associated with a high incidence of VTE in patients with cancer warranting further investigation.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993595","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":"Dual role of Metrnl: exercise-induced benefits and potential cancer implications.","authors":"Hamid Alizadeh","doi":"10.1136/jitc-2025-011666","DOIUrl":"10.1136/jitc-2025-011666","url":null,"abstract":"<p><p>Metrnl (Meteorin-like), a protein elevated by exercise, supports metabolic regulation, inflammation reduction and glucose homeostasis. While exercise is a cornerstone of cancer prevention and management, recent findings suggest that Metrnl plays a dual role, potentially impairing T-cell function in the tumor microenvironment. This commentary explores the interplay between Metrnl's systemic benefits and its local immunosuppressive effects in cancer. Despite these concerns, exercise remains broadly advantageous for patients with cancer, though further research is essential to understand Metrnl's context-specific impacts.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993594","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":"PD-1 blockade employed at the time CD8+ T cells are activated enhances their antitumor efficacy.","authors":"Jena E Moseman, Ichwaku Rastogi, Donghwan Jeon, Douglas G McNeel","doi":"10.1136/jitc-2024-011145","DOIUrl":"https://doi.org/10.1136/jitc-2024-011145","url":null,"abstract":"<p><strong>Background: </strong>We have previously shown that immune checkpoint receptors, including PD-1, are upregulated on T cells at the time of their activation, and that blockade of these receptors can improve the efficacy of antitumor vaccines. In the present study, we sought to determine whether, and by what mechanisms, the timing of PD-1 blockade with respect to vaccination affects antitumor T cell function.</p><p><strong>Methods: </strong>TRAMP-C1 or E.G7-OVA tumor-bearing mice received PD-1 blockade at different timing intervals with a tumor-associated antigen vaccine. Tumor growth, survival, and immune-infiltrating populations were assessed. In vitro models of T cell activation using OT-I T cells and PD-(L)1 axis disruption with a PD-1 blocking antibody or PD-L1^KO dendritic cells were used.</p><p><strong>Results: </strong>Mice receiving PD-1 blockade at the time of T cell activation with vaccine had better antitumor outcomes in comparison to mice receiving PD-1 blockade before or after immunization. T cells activated in vitro in the presence of PD-(L)1 axis disruption had a more differentiated, functional phenotype with decreased CD28 and CCR7 expression and increased production of the Tc1 cytokines IL-2, TNFα, and IFNγ. Intriguingly, a small subset of undifferentiated cells (CD28+) was of a stem-like Tc17 phenotype (IL-17α+, TCF1+). Tumor-bearing mice receiving T cells activated in the presence of PD-(L)1-axis disruption had better antitumor outcomes and a greater number of complete responses.</p><p><strong>Conclusions: </strong>These data indicate that PD-1 blockade, when used with antitumor vaccines, acts primarily at the time of T cell activation, not exclusively within the tumor microenvironment. Consequently, PD-1 blockade may be best used when delivered concurrently with T cell activating agents such as vaccines.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024542","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":"Early dynamics of clinical and laboratory parameters predict primary refractory disease in patients with metastatic urothelial carcinoma receiving atezolizumab.","authors":"Christopher J Graser, Thomas O McDonald, Paul J Catalano, Guru Sonpavde, Franziska Michor","doi":"10.1136/jitc-2025-011740","DOIUrl":"10.1136/jitc-2025-011740","url":null,"abstract":"<p><strong>Background: </strong>In patients with metastatic urothelial carcinoma (mUC) receiving programmed cell death ligand 1 (PD-L1) inhibitors, it is critically important to identify primary refractory patients very early to enable modification of therapy before clinical progression and decline of performance status. We hypothesized that baseline and early-on-treatment (EOT) parameters may help identify patients likely to have primary refractory disease.</p><p><strong>Methods: </strong>We considered baseline and EOT variables measured up to 5 weeks after initiating therapy in the phase 3 clinical trial IMvigor211, which compared atezolizumab versus chemotherapy, in muC patients who had progressed on platinum-based chemotherapy. We used least absolute shrinkage and selection operator-regularized logistic regression models to predict the risk of primary refractory disease employing clinical and laboratory variables.</p><p><strong>Results: </strong>902 patients were evaluable for analysis. Our baseline model achieves an area under the curve (AUC) of 0.730, 0.717 for the atezolizumab group and 0.696 for the chemotherapy group. The AUC increases to 0.848 overall with EOT parameters, 0.871 for the atezolizumab group and 0.788 for the chemotherapy group. The EOT model suggests that 33.7% of patients receiving atezolizumab may benefit from switching to chemotherapy, reducing their risk of primary refractoriness from 67.1% to 51.5%.</p><p><strong>Conclusions: </strong>Our prediction model employs readily available and routinely measured clinical and laboratory factors, such as urine-specific gravity, presence of liver metastases, and total protein and erythrocyte counts. It robustly identifies patients with early primary refractory disease to atezolizumab before clinical progression and may inform therapeutic decisions. Validation in larger independent cohorts and other treatments is required.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972223","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":"BCL-2 mutant B7H6-CAR-T cells synergized with venetoclax for treating small cell lung cancer.","authors":"Huihui Zhang, Liliang Xia, Wendi Xuzhang, Ziming Li, Junshi Zhang, Fanlin Li, Chen Cheng, Jiawen Wang, Xincheng Zong, Xuanming Yang, Shun Lu","doi":"10.1136/jitc-2024-010073","DOIUrl":"https://doi.org/10.1136/jitc-2024-010073","url":null,"abstract":"<p><strong>Background: </strong>Patients with small cell lung cancer (SCLC) generally have a poor prognosis, with an exceptionally high proliferative rate and a strong propensity for early metastasis, indicating the urgent need for novel therapies. The development of chimeric antigen receptor (CAR)s targeting solid tumors is limited owing to the lack of target antigens and low efficacy. In this study, we aimed to discover new targets for SCLC CAR-T therapy and develop CAR-T-based combinational treatment against SCLC in preclinical models.</p><p><strong>Methods: </strong>The in vitro antitumor activity of B7H6-specific CAR-T cell was evaluated. Venetoclax-resistant B7H6 CAR-T cell were designed and the synergistic effect of venetoclax and B7-H6 CAR-T cells was tested in vitro and in vivo.</p><p><strong>Result: </strong>B7H6 is highly expressed in SCLC tumors. CAR-T cell against B7H6 displayed antigen-specific antitumor efficacy. BCL-2(D103E)-expressing CAR-T cells showed resistance to venetoclax-induced apoptosis. The combinational treatment of venetoclax and BCL-2(D103E)-expressing B7H6-targeting showed potent anti-SCLC effect in vitro and in vivo.</p><p><strong>Conclusions: </strong>Our findings suggest that the combination of BCL-2 mutant-expressing B7H6-targeting CAR-T cells and venetoclax could be a promising novel strategy against B7H6-expressing SCLCs and other solid tumors, providing the foundation for CAR-T cells and proapoptotic small molecules therapy in patients with SCLCs in a clinical trial.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001093","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":"Development and optimization of Eva1 (<i>MPZL2</i>) targeting chimeric antigen receptor T cells.","authors":"Masahide Osaki, Seitaro Terakura, Shiho Hirano, Takuma Iwasa, Kanako C Hatanaka, Yutaka Hatanaka, Masaki Sunagawa, Toshio Kokuryo, Yoshitaka Adachi, Yuki Takeuchi, Ryo Hanajiri, Chie Sakanaka, Makoto Murata, Tomoki Ebata, Hitoshi Kiyoi","doi":"10.1136/jitc-2024-009825","DOIUrl":"https://doi.org/10.1136/jitc-2024-009825","url":null,"abstract":"<p><strong>Background: </strong>Whereas chimeric antigen receptor gene modified T (CAR-T) cell therapy has been clinically applied to malignant lymphomas and multiple myeloma, CAR-T cell therapy for solid tumors has so far not reached clinical application. Epithelial V-like antigen 1 (Eva1), transcribed from <i>myelin protein zero-like 2 (MPZL2),</i> is a small surface protein highly expressed on various tumor cells. We selected Eva1 as a novel solid tumor-target antigen because of its broad expression across various tumor types. The purpose of the present study is to develop and optimize CAR-T cells targeting Eva1.</p><p><strong>Method: </strong>We prepared various humanized single chain variable fragment sequences based on a mouse anti-human Eva1 monoclonal antibody. We constructed six humanized Eva1CAR-Ts and selected one that maintained specificity and good cellular proliferation after antigen stimulation. We further optimized the length of the extracellular spacer domain and the choice of the intracellular domain in vitro and in two different xenograft mouse models.</p><p><strong>Results: </strong>We confirmed Eva1 expression on various tumor cell lines by flow cytometry and analysis of public database, but we also observed that normal monocytes weakly expressed Eva1. A combination of short spacer domain and 4-1BB or CD79A/CD40 intracellular domain provided higher treatment efficacy both in vitro and in vivo. The cytokine release on autologous monocyte stimulation to Eva1CAR-T cells was comparable to that on autologous B cell stimulation to CD19CAR-T cells. Humanized Eva1CAR-T cells demonstrated excellent therapeutic efficacy by infusing a single dose of Eva1CAR-T cells (1×10⁶) in both NCI-H1975 lung cancer and CFPAC-1 pancreatic cancer cell line grafted model.</p><p><strong>Conclusions: </strong>In summary, these data suggest that humanized Eva1CAR-T has promising therapeutic potential for the treatment of various Eva1-positive solid tumors. Regarding on-target/off-tumor recognition, further detailed analyses of the Eva1CAR-T cell responses to normal tissues are needed.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012538","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":"Correspondence on 'Characteristics of second primary malignancies following bispecific antibodies therapy' by Liang <i>et al</i>.","authors":"Yan Jin, Yongli Jin, Yan Cui, Rongzhen Zheng","doi":"10.1136/jitc-2025-012384","DOIUrl":"10.1136/jitc-2025-012384","url":null,"abstract":"<p><p>We commend Liang <i>et al</i> for shining a spotlight on second primary malignancies after bispecific antibody (BsAb) therapy, yet several clinical nuances deserve consideration. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS)-derived case-fatality rates likely overstate risk, prior genotoxic treatments confound causality, and pooling heterogeneous BsAb constructs may blur construct-specific signals. The 124-day median latency hints at misclassification, while sparse African data limit global relevance. Risk-adapted surveillance-grounded in clonal haematopoiesis, prior cytotoxic exposure and BsAb construct-may be more pragmatic than blanket monitoring.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12161387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997547","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 enhancement of CAR-NK cells through non-viral engineering and highly multiplexed base editing.","authors":"Minjing Wang, Joshua B Krueger, Alexandria K Gilkey, Erin M Stelljes, Mitchell G Kluesner, Emily J Pomeroy, Joseph G Skeate, Nicholas J Slipek, Walker S Lahr, Patricia N Claudio Vázquez, Yueting Zhao, Jason B Bell, Kendell Clement, Ella J Eaton, Kanut Laoharawee, Jae-Woong Chang, Beau R Webber, Branden S Moriarity","doi":"10.1136/jitc-2024-009560","DOIUrl":"https://doi.org/10.1136/jitc-2024-009560","url":null,"abstract":"<p><strong>Background: </strong>Natural killer (NK) cells' unique ability to kill transformed cells expressing stress ligands or lacking major histocompatibility complexes (MHC) has prompted their development for immunotherapy. However, NK cells have demonstrated only moderate responses against cancer in clinical trials.</p><p><strong>Methods: </strong>Advanced genome engineering may thus be used to unlock their full potential. Multiplex genome editing with CRISPR/Cas9 base editors (BEs) has been used to enhance T cell function and has already entered clinical trials but has not been reported in human NK cells. Here, we report the first application of BE in primary NK cells to achieve both loss-of-function and gain-of-function mutations.</p><p><strong>Results: </strong>We observed highly efficient single and multiplex base editing, resulting in significantly enhanced NK cell function in vitro and in vivo. Next, we combined multiplex BE with non-viral <i>TcBuster</i> transposon-based integration to generate interleukin-15 armored CD19 chimeric antigen receptor (CAR)-NK cells with significantly improved functionality in a highly suppressive model of Burkitt's lymphoma both in vitro and in vivo.</p><p><strong>Conclusions: </strong>The use of concomitant non-viral transposon engineering with multiplex base editing thus represents a highly versatile and efficient platform to generate CAR-NK products for cell-based immunotherapy and affords the flexibility to tailor multiple gene edits to maximize the effectiveness of the therapy for the cancer type being treated.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024958","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":"PDZ domains of PATJ facilitate immunological synapse formation to promote T cell activation.","authors":"Xinxin Xiong, Danyang Wang, Liping Xu, Siyu Chen, Jingjing He, Xiaomin Zhang, Ziqian Fang, Jianeng Zhang, Wende Li, Penghui Zhou","doi":"10.1136/jitc-2024-010966","DOIUrl":"https://doi.org/10.1136/jitc-2024-010966","url":null,"abstract":"<p><strong>Background: </strong>The highly organized structures of the immunological synapse (IS) are crucial for T cell activation. PDZ domains might be involved in the formation of the IS by serving as docking sites for protein interactions. In this study, we investigate the role of the PALS1-associated tight junction protein (PATJ), which contains 10 PDZ domains, in the formation of IS and its subsequent impact on T cell activation.</p><p><strong>Methods: </strong>To elucidate the function of PATJ, we generated murine models with conditional T cell-specific knockout of <i>Patj</i> and assessed T cell activation both <i>in vitro</i> and <i>in vivo</i> within the context of infection and cancer. We employed confocal microscopy to visualize the formation of IS between T cells and antigen-presenting cells in the absence of <i>Patj</i>. A series of PATJ truncations containing different combinations of PDZ domains was used to identify the minimal domain required for effective T cell receptor signaling. The identified active PDZ domain was then incorporated into mesothelin (MSLN)-specific chimeric antigen receptor (CAR) to evaluate its impact on CAR-T cell cytotoxicity against solid tumors.</p><p><strong>Results: </strong>We observed a rapid increase in PATJ expression during T cell activation. Conditional knockout of <i>Patj</i> in T cells showed impaired immunity against infection and cancer in murine models. Mechanistically, ablation of <i>Patj</i> impedes IS formation, and thus reduces T cell activation. We further showed that engineering the active PDZ domain of PATJ into CAR structure significantly promoted the effector function of CAR-T cells.</p><p><strong>Conclusions: </strong>Our study reveals an important role of PATJ in the formation of IS and provides an approach to improve the efficacy of CAR-T therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12060881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144021209","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}