Gabriel Espinosa-Carrasco, Edison Chiu, Aurora Scrivo, Paul Zumbo, Asim Dave, Doron Betel, Sung Wook Kang, Hee-Jin Jang, Matthew D. Hellmann, Bryan M. Burt, Hyun-Sung Lee, Andrea Schietinger
{"title":"Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors","authors":"Gabriel Espinosa-Carrasco, Edison Chiu, Aurora Scrivo, Paul Zumbo, Asim Dave, Doron Betel, Sung Wook Kang, Hee-Jin Jang, Matthew D. Hellmann, Bryan M. Burt, Hyun-Sung Lee, Andrea Schietinger","doi":"10.1016/j.ccell.2024.05.025","DOIUrl":null,"url":null,"abstract":"<p>Tumor-specific CD8<sup>+</sup> T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4<sup>+</sup> T cells can be enlisted to overcome CD8<sup>+</sup> T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8<sup>+</sup> and CD4<sup>+</sup> T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4<sup>+</sup> T cells must engage with CD8<sup>+</sup> T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8<sup>+</sup> T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8<sup>+</sup> and CD4<sup>+</sup> T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4<sup>+</sup> T cells and triads are required for CD8<sup>+</sup> T cell cytotoxicity during the effector phase and tumor elimination.</p>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":null,"pages":null},"PeriodicalIF":48.8000,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ccell.2024.05.025","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ T cells can be enlisted to overcome CD8+ T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4+ T cells must engage with CD8+ T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8+ and CD4+ T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4+ T cells and triads are required for CD8+ T cell cytotoxicity during the effector phase and tumor elimination.
肿瘤特异性 CD8+ T 细胞经常功能失调,无法阻止肿瘤生长。我们研究了能否利用肿瘤特异性 CD4+ T 细胞来克服肿瘤内 CD8+ T 细胞的功能障碍。我们发现,CD8+和CD4+ T细胞的空间定位和相互作用,而不是它们的数量,决定了采用T细胞疗法和免疫检查点阻断(ICB)时的抗肿瘤反应:在效应阶段,CD4+ T 细胞必须与同一树突状细胞上的 CD8+ T 细胞接触,形成三细胞型细胞簇(三联体),才能发挥 CD8+ T 细胞的细胞毒性并消灭癌细胞。当瘤内三联体形成被破坏时,尽管肿瘤特异性 CD8+ 和 CD4+ T 细胞的数量相等,肿瘤仍会发展。在接受 ICB 治疗的胸膜间皮瘤患者中,三联体与临床反应相关。因此,CD4+ T 细胞和三联体是 CD8+ T 细胞在效应期发挥细胞毒性和消除肿瘤所必需的。
期刊介绍:
Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows:
Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers.
Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice.
Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers.
Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies.
Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.