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

Li, Wenwen; Lu, Lu; Lü, Juanjuan; Wang, Xinran; Yang, Chao; Jin, Jingsi; Wu, Lingling; Hong, Xiaochuan; Li, Fanlin; Cao, Dongqing; Yang, Yong; Wu, Meng; Su, Bing; Cheng, Jinke; Yang, Xuanming; Di, Wen; Deng, Lu

doi:10.1126/scitranslmed.aay9013

Cited by 151 publications

(116 citation statements)

References 59 publications

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“…A compromised expression of the cGAS-STING cascade has also been confirmed in CD8+T cells from cancer patients, with reduced stem-like central memory CD8+T cells subsets ( 35 ). This is a selective advantage for survival and growth for cancers ( 36 ).…”

Section: Introductionmentioning

confidence: 90%

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

et al. 2020

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Upon recognition of microbial DNA or self-DNA, the cyclic-GMP-AMP synthase (cGAS) of the host catalyzes the production of the cyclic dinucleotide cGAMP. cGAMP is the main activator of STING, stimulator of interferon genes, leading to interferon synthesis through the STING-TBK1-IRF3 pathway. STING is also a hub for activation of NF-κB and autophagy. The present review details the striking similarities between T and B cell responses in severe coronavirus disease 2019 (COVID-19) and both animal or human models of STING gain of function (SAVI syndromes: STING-associated vasculopathy with onset in infancy). Those similarities may be further clues for a delayed activation of STING in severe COVID-19 patients, due to DNA damages following severe acute respiratory syndrome coronaviruses (SARS-CoV-2) infection and unusual role of STING in SARS-CoV-2 control. In early stages, Th2 differentiation are noticed in both severe COVID-19 and SAVI syndromes; then, CD4+ and CD8+ T cells functional exhaustion/senescent patterns due to TCR hyper-responsiveness are observed. T cell delayed over-responses can contribute to pneumonitis and delayed cytokine secretion with over-production of IL-6. Last, STING over-activation induces progressive CD4+ and CD8+ T lymphopenia in SAVI syndromes, which parallels what is observed in severe COVID-19. ACE2, the main receptor of SARS-CoV-2, is rarely expressed in immune cells, and it has not been yet proven that some human lymphocytes could be infected by SARS-CoV-2 through CD147 or CD26. However, STING, expressed in humans T cells, might be triggered following excessive transfer of cGAMP from infected antigen presenting cells into activated CD4+ and CD8+ T cells lymphocytes. Indeed, those lymphocytes highly express the cGAMP importer SLC19A1. Whereas STING is not expressed in human B cells, B cells counts are much less affected, either in COVID-19 or SAVI syndromes. The recognition of delayed STING over-activation in severe COVID-19 patients could prompt to target STING with specific small molecules inhibitors already designed and/or aspirin, which inhibits cGAS.

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Section: Introductionmentioning

confidence: 90%

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

et al. 2020

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“…Finally, tumor cell-derived cGAMP can also be transferred to host DCs by the folate transporter SLC19A1 and then directly binds to STING, activating it in DCs [ 84 ]. A recent study more directly demonstrated that cell-autonomous STING promoted the maintenance of stem cell-like CD8 + T cells and augmented antitumor T cell responses, and mechanistically, cGAS-STING-mediated type I interferon signaling reinforced the stem cell–like CD8 + T cell differentiation program mainly by restraining Akt activity [ 85 ].…”

Section: The Antitumor Functions Of the Cgas-sting Signaling Pathwaymentioning

confidence: 99%

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

et al. 2020

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Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.

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“…CC-BY-NC-ND 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made The copyright holder for this preprint this version posted March 8, 2021. ; https://doi.org/10.1101/2021.03.08.434225 doi: bioRxiv preprint 14 thereby increases innate and adaptive immune signaling in tumors (33). The cGAS-STING pathway is emerging as a key regulator of cancer development and therapeutic response with roles in tumor development, metastasis, immunomodulation, senescence, viral defense, and autophagy (34)(35)(36)(37)(38)(39)(40).…”

mentioning

confidence: 99%

Atrxdeletion impairs cGAS-STING signaling and increases response to radiation and oncolytic herpesvirus in sarcoma

Floyd

Pierpoint

et al. 2021

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ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx deleted tumors are more sensitive to radiation therapy. In the absence of Atrx, irradiated sarcomas have increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. We find that Atrx deleted sarcomas have a reduced adaptive immune response, impaired cGAS-STING signaling, and increased sensitivity to an oncolytic herpesvirus therapy. Translation of these results to patients with ATRX mutant cancers could enable genomically-guided cancer therapeutic approaches that improve patient outcomes.

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

Cited by 151 publications

References 59 publications

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

Atrxdeletion impairs cGAS-STING signaling and increases response to radiation and oncolytic herpesvirus in sarcoma

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

Cited by 151 publications

References 59 publications

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

Lymphocyte Changes in Severe COVID-19: Delayed Over-Activation of STING?

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

Atrxdeletion impairs cGAS-STING signaling and increases response to radiation and oncolytic herpesvirus in sarcoma

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