Research ArticleCancer

cGAS-STING–mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy

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Science Translational Medicine  24 Jun 2020:
Vol. 12, Issue 549, eaay9013
DOI: 10.1126/scitranslmed.aay9013

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Intuitive CD8+ T cells sense DNA

Stimulator of interferon genes (STING) agonism is an area of active exploration for cancer immunotherapy. Li et al. examined the cGAS-STING DNA sensing cascade in antitumor CD8+ T cells. They observed dampened STING activity in CD8+ T cells from patients with cancer or mice implanted with tumors. STING signaling supported a stem-like memory phenotype in the T cells, which is known to be beneficial for responses to immunotherapy. Cytosolic DNA was enriched in activated T cells, and STING agonism improved efficacy of adoptive cell therapy in multiple mouse models. These results highlight that CD8+ T cell DNA sensing could be exploited for therapeutic benefit in immunotherapy.

Abstract

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.

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