cGAS-STING-mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy
- 24 June 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 12 (549)
- https://doi.org/10.1126/scitranslmed.aay9013
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.Funding Information
- National Natural Science Foundation of China (81771682)
- National Natural Science Foundation of China (81702804)
- National Natural Science Foundation of China (31900649)
- Science and Technology Commission of Shanghai Municipality (16JC1406000)
- Shanghai Municipal Commission of Health and Family Planning
- Shanghai Municipal Health Commission (20194Y0625)
- Innovative Research Team of High-Level Local Universities in Shanghai
- National Thousand Youth Talents Program
This publication has 54 references indexed in Scilit:
- The Cytosolic DNA-Sensing cGAS–STING Pathway in CancerCancer Discovery, 2020
- PARP Inhibitor Efficacy Depends on CD8+ T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast CancerCancer Discovery, 2019
- Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung CancerCancer Discovery, 2019
- cGAS in action: Expanding roles in immunity and inflammationScience, 2019
- Design of amidobenzimidazole STING receptor agonists with systemic activityNature, 2018
- A Paradigm Shift in Cancer Immunotherapy: From Enhancement to NormalizationCell, 2018
- LC3-Associated Phagocytosis in Myeloid Cells Promotes Tumor Immune ToleranceCell, 2018
- Mitotic progression following DNA damage enables pattern recognition within micronucleiNature, 2017
- CD47 blockade triggers T cell–mediated destruction of immunogenic tumorsNature Medicine, 2015
- STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic TumorsImmunity, 2014