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cGAS-STING–mediated DNA sensing maintains CD8 + T cell stemness and promotes antitumor T cell therapy
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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“Also, two recent reports have shown that T cell-intrinsic STING signaling could control differentiation and effector functions of CD8+ and CD4+ T cells60,61.”
From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [61]
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Metadata
- Authors
- Li, W., Lu, L., Lu, J., Wang, X., Yang, C., Jin, J., Wu, L., Hong, X., Li, F., Cao, D., Yang, Y., Wu, M., Su, B., Cheng, J., Yang, X., Di, W., & Deng, L.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Corresponding author
- Li, Wenwen
- Lu, Lu
- Yang, Xuanming
- Di, Wen
- Deng, Liufu
- ORCID
- Venue
- Science Translational Medicine
- Published
- 2020-06-24
- Volume
- 12
- Issue
- 549
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W3038007966
- Cited by
- 305
- References
- 54
- Citations by year
- 2026: 62 · 2025: 75 · 2024: 56 · 2023: 45 · 2022: 39 · 2021: 21 · 2020: 7
- FWCI
- 9.79
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81771682, 81702804, 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
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- cGAS-STING pathway, DNA sensing, CD8+ T cells, T cell stemness, antitumor immunity, CAR T-cell therapy, cancer immunotherapy
- MeSH terms
- Animals, DNA, Humans, Membrane Proteins, Nucleotidyltransferases, CD8-Positive T-Lymphocytes, Mice, Cell- and Tissue-Based Therapy
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