{"title":"Targeting PD-1 and CD85j can restore intratumoral CD4<sup>+</sup> GzmB<sup>+</sup> T-cell functions to combat MHC-II-expressing tumors.","authors":"Boyu Wang, Xu Wang, Tianlai Wang, Kelin Meng, Taiyan Yu, Yu Xi, Shaojie Hu, Hui Xiong, Rirong Qu, Zhiwei Yuan, Xue Wang, Chenxi Zeng, Wenbin Zou, Yitao Tian, Yixin Cai, Shengling Fu, Xiangning Fu, Lequn Li","doi":"10.1136/jitc-2024-010890","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>A subset of CD4<sup>+</sup> T cells with cytotoxic activity has been identified, and these cells exert their effects by expressing perforin and granzymes. Despite the progress made in characterizing cytotoxic CD4<sup>+</sup> T cells in various diseases, the status of cytotoxic CD4<sup>+</sup> T cells in non-small cell lung cancer (NSCLC) and the underlying mechanisms involved in promoting intratumoral cytotoxic CD4<sup>+</sup> T-cell activation remain unclear.</p><p><strong>Methods: </strong>We used flow cytometry to examine the phenotypic and functional properties of CD4<sup>+</sup>GzmB<sup>+</sup> T cells in the peripheral blood and tumor tissues of patients with NSCLC. Loss-of-function analyses and RNA sequencing were used to identify the underlying mechanisms involved in the effects of interleukin (IL)-15 on the restoration of CD4<sup>+</sup>GzmB<sup>+</sup> T-cell function in vitro. A patient-derived lung cancer explant model and an animal model were used to verify the effects of immune checkpoint inhibitors on CD4<sup>+</sup>GzmB<sup>+</sup> T-cell activation.</p><p><strong>Results: </strong>In patients with NSCLC, impaired cytolytic function of tumor-infiltrated granzyme B (GzmB)-expressing CD4<sup>+</sup> T cells was restored by IL-15 through activation of the AKT-FOXO1-T-bet axis. Moreover, IL-15 stimulation increased solute carrier family 7 member 5 (SLC7A5) expression in CD4<sup>+</sup>GzmB<sup>+</sup> T cells in an Protein Kinase B (AKT)-dependent manner, and inhibition of SLC7A5 abrogated the effect of IL-15 on CD4<sup>+</sup>GzmB<sup>+</sup> T cells. Additionally, we showed that the immune checkpoint molecules programmed cell death-1 (PD-1) and CD85j were mutually exclusively expressed in CD4<sup>+</sup>GzmB<sup>+</sup> T cells and that dual targeting of PD-1 and CD85j enhanced the effector function of CD4<sup>+</sup>GzmB<sup>+</sup> T cells by activating the AKT pathway. Notably, tumor cells expressing major histocompatibility complex (MHC)-II and IL-15 determine the effectiveness of CD4<sup>+</sup>GzmB<sup>+</sup> T-cell-mediated antitumor immunity in response to immunotherapy.</p><p><strong>Conclusions: </strong>Our study demonstrated that tumor-infiltrating CD4<sup>+</sup>GzmB<sup>+</sup> T cells fail to eliminate tumors. Dual blockade of PD-1 and CD85j alongside IL-15 restores the effector function of CD4<sup>+</sup>GzmB<sup>+</sup> T cells and drives CD4<sup>+</sup>GzmB<sup>+</sup> T-cell transformation in the tumor microenvironment to combat MHC-II-expressing tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 4","pages":""},"PeriodicalIF":10.3000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal for Immunotherapy of Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jitc-2024-010890","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: A subset of CD4+ T cells with cytotoxic activity has been identified, and these cells exert their effects by expressing perforin and granzymes. Despite the progress made in characterizing cytotoxic CD4+ T cells in various diseases, the status of cytotoxic CD4+ T cells in non-small cell lung cancer (NSCLC) and the underlying mechanisms involved in promoting intratumoral cytotoxic CD4+ T-cell activation remain unclear.
Methods: We used flow cytometry to examine the phenotypic and functional properties of CD4+GzmB+ T cells in the peripheral blood and tumor tissues of patients with NSCLC. Loss-of-function analyses and RNA sequencing were used to identify the underlying mechanisms involved in the effects of interleukin (IL)-15 on the restoration of CD4+GzmB+ T-cell function in vitro. A patient-derived lung cancer explant model and an animal model were used to verify the effects of immune checkpoint inhibitors on CD4+GzmB+ T-cell activation.
Results: In patients with NSCLC, impaired cytolytic function of tumor-infiltrated granzyme B (GzmB)-expressing CD4+ T cells was restored by IL-15 through activation of the AKT-FOXO1-T-bet axis. Moreover, IL-15 stimulation increased solute carrier family 7 member 5 (SLC7A5) expression in CD4+GzmB+ T cells in an Protein Kinase B (AKT)-dependent manner, and inhibition of SLC7A5 abrogated the effect of IL-15 on CD4+GzmB+ T cells. Additionally, we showed that the immune checkpoint molecules programmed cell death-1 (PD-1) and CD85j were mutually exclusively expressed in CD4+GzmB+ T cells and that dual targeting of PD-1 and CD85j enhanced the effector function of CD4+GzmB+ T cells by activating the AKT pathway. Notably, tumor cells expressing major histocompatibility complex (MHC)-II and IL-15 determine the effectiveness of CD4+GzmB+ T-cell-mediated antitumor immunity in response to immunotherapy.
Conclusions: Our study demonstrated that tumor-infiltrating CD4+GzmB+ T cells fail to eliminate tumors. Dual blockade of PD-1 and CD85j alongside IL-15 restores the effector function of CD4+GzmB+ T cells and drives CD4+GzmB+ T-cell transformation in the tumor microenvironment to combat MHC-II-expressing tumors.
期刊介绍:
The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.