cGAS-STING–mediated DNA sensing maintains CD8 + T cell stemness and promotes antitumor T cell therapy
| Autor: | Chao Yang, Yuanqin Yang, Dongqing Cao, Xinran Wang, Fanlin Li, Xuanming Yang, Juanjuan Lu, Bing Su, Jinke Cheng, Meng Wu, Xiaochuan Hong, Jingsi Jin, Liufu Deng, Lingling Wu, Wen Di, Lu Lu, Wenwen Li |
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| Rok vydání: | 2020 |
| Předmět: | |
| Zdroj: | Science Translational Medicine. 12 |
| ISSN: | 1946-6242 1946-6234 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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