cGAS-STING-mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy
cGAS-STING-mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy
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cGAS-STING 介导的 DNA 传感可维持 CD8(+) T 细胞干性并促进抗肿瘤 T 细胞治疗。
DOI：
10.1126/scitranslmed.aay9013
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发表时间：
2020-06-24
影响因子：
17.1
通讯作者：
Deng, Liufu
中科院分区：
文献类型：
--
作者：
Li, Wenwen;Lu, Lu;Deng, Liufu
尽管肿瘤细胞或吞噬细胞中由cGAS - STING介导的DNA感应对于启动抗肿瘤免疫至关重要，但T细胞中固有cGAS - STING激活的作用仍不明确。在此，我们观察到癌症患者的外周血CD8(+) T细胞中cGAS - STING级联的表达显著受损。我们证明了过继转移的CD8(+) T细胞中的cGAS - STING级联对于小鼠T细胞治疗背景下的抗肿瘤免疫反应至关重要。从机制上讲，细胞自主性的cGAS和STING部分通过调节转录因子TCF1的表达促进了干细胞样CD8(+) T细胞的维持。此外，自分泌的cGAS - STING介导的I型干扰素信号主要通过抑制Akt活性增强了干细胞样CD8(+) T细胞的分化程序。此外，在体外和体内刺激下，基因组DNA在小鼠CD8(+) T细胞的胞质中选择性富集。STING激动作用增强了癌症患者中干细胞样中央记忆CD8(+) T细胞的形成，并在异种移植模型中增强了CAR - T细胞治疗的抗肿瘤反应。这些发现增进了我们对T细胞中固有cGAS - STING激活的理解，并为通过利用cGAS - STING通路进行癌症免疫治疗来开发改进的T细胞疗法提供了思路。
Although cGAS-STING-mediated DNA sensing in tumor cells or phagocytes is central for launching antitumor immunity, the role of intrinsic cGAS-STING activation in T cells remains unknown. Here, we observed that peripheral blood CD8(+) T cells from patients with cancer showed remarkably compromised expression of the cGAS-STING cascade. We demonstrated that the cGAS-STING cascade in adoptively transferred CD8(+) T cells was essential for antitumor immune responses in the context of T cell therapy in mice. Mechanistically, cell-autonomous cGAS and STING promoted the maintenance of stem cell-like CD8(+) T cells, in part, by regulating the transcription factor TCF1 expression. Moreover, autocrine cGAS-STING-mediated type I interferon signaling augmented stem cell-like CD8(+) T cell differentiation program mainly by restraining Akt activity. In addition, genomic DNA was selectively enriched in the cytosol of mouse CD8(+) T cells upon in vitro and in vivo stimulation. STING agonism enhanced the formation of stem-like central memory CD8(+) T cells from patients with cancer and potentiated antitumor responses of CAR-T cell therapy in a xenograft model. These findings advance our understanding of inherent cGAS-STING activation in T cells and provide insight into the development of improved T cell therapy by harnessing the cGAS-STING pathway for cancer immunotherapy.