Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors

IF 48.8 1区 医学 Q1 CELL BIOLOGY
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
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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.

Abstract Image

免疫疗法介导的实体瘤消除需要瘤内免疫三联体
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。
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来源期刊
Cancer Cell
Cancer Cell 医学-肿瘤学
CiteScore
55.20
自引率
1.20%
发文量
179
审稿时长
4-8 weeks
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.
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