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Cited by 85T-cell and B-cell ImmunologyCancer Immunotherapy and Biomarkersinterferon and immune responses

T cell-intrinsic STING signaling promotes regulatory T cell induction and immunosuppression by upregulating FOXP3 transcription in cervical cancer

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Ni, Huanhe, Zhang, Huanling, Li, Lin, Huang, He, Guo, Hui, Zhang, Lin, Li, Chunwei, Xu, Jing-Xiao +5 more·2022·Journal for ImmunoTherapy of Cancer
DOI 10.1136/jitc-2022-005151PMC PMC9490630
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Abstract

Background: Stimulator of interferon genes (STING) is an innate immune sensor of cytoplasmic double-stranded DNA originating from microorganisms and host cells. The activation of cytosolic DNA-STING pathway in tumor microenvironments is usually linked to more robust adaptive immune responses to tumors, however the intracellular function of STING in regulatory T cells is largely unknown. In the present study, we aimed to explore the contribution of intracellular STING activation to regulatory T cell induction (iTreg) in cervical cancer (CC) microenvironments. Methods: Blood samples and tumor specimens were obtained from patients with CC. The intratumoral STING, CCL22, CD8 and forkhead box P3 (FOXP3) expression levels were measured by immunohistochemistry. T cell-specific STING conditional knockout mice (CD4-Cre/STING flox/flox , TKO) were generated, and syngeneic TC-1 tumor model were investigated. The differentiation and molecular regulatory pathway of human and murine iTreg under different treatments were investigated by ex vivo assays, immunoblotting and quantitative PCR. Tumor-associated exosomes (T-EXO) were isolated from CC cell lines and exosomal contents were identified by ELISA and Western blot analysis. The impact of T-EXO on T cell differentiation was tested in in vitro cell culture. Results: Increased STING, CCL22 level, FOXP3 + cells but decreased CD8 + cells in tumor tissues predicted poor survival. Tumor-bearing CD4-Cre-STING flox/flox (TKO) mice displayed slower tumor growth tendencies as well as fewer FOXP3 + cells but higher CD8 + cell proportion in tumor tissues than wild-type (WT) mice. Activating of STING signaling cooperated with T cell receptor, interleukin-2 receptor and transforming growth factor-beta (TGF-β) signals to promote CD4 + CD25 high FOXP3 + iTreg differentiation from both human and murine CD4 + -naïve T cells from WT and IFNAR −/− mice but not TKO or IRF3 −/− mice in vitro. Ectopic STING, TBK1 or IRF3 expression promoted iTreg differentiation from human CD4 + -naïve T cells. T cell-intrinsic STING activation induced FOXP3 transcription through TBK1-IRF3-mediated SMAD3 and STAT5 phosphorylation independent of interferon-β. In CC, tumor-derived exosomes activated STING signaling in tumor-infiltrated T cells by exosomal TGF-β, cyclic GMP-AMP synthase and 2’-3’-cGAMP, leading to iTreg expansion. Conclusions: These findings highlight a novel mechanism for iTreg expansion mediated by tumor-derived exosome-activated T cell-intrinsic STING signal, and provide a rationale for developing immunotherapeutic strategies targeting STING signal in CC.

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  • The current dogma dictates that the host-derived STING pathway is the converging critical responder.

    “a finding that is in sharp contrast to the current dogma which dictates that host-derived STING pathway is the converging critical responder.79–81”

    From Functional tumor cell-intrinsic STING, not host STING, drives local and systemic antitumor immunity and therapy efficacy following cryoablation (2023) · cites this paper as [79]

    The Introduction (page unavailable) says STING signaling in immune cells is needed for type I IFN-dependent T-cell priming and NK-cell cytotoxicity, supporting an important role for host-cell STING in antitumor immunity. It does not establish the broader claim that host-derived STING is the converging critical responder; the Discussion (page unavailable) also describes a distinct role for T-cell-intrinsic STING. (LLM, conf=0.78)

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Cited by

Sorted by citations

Authors
Ni, H., Zhang, H., Li, L., Huang, H., Guo, H., Zhang, L., Li, C., Xu, J.-X., Nie, C.-P., Li, K., Zhang, X., Xia, X., & Li, J.
Affiliations
  • State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
  • Sun Yat-sen University (CN)
  • Sun Yat-sen University Cancer Center (CN)
Corresponding author
  • Xia, Xiaojun
  • Li, Jiang
ORCID
Venue
Journal for ImmunoTherapy of Cancer
Publisher
BMJ
Published
2022-09
Volume
10
Issue
9
Pages
e005151
ISSN
2051-1426 (ISSN-L)
DOI
10.1136/jitc-2022-005151
PMC
PMC9490630
OpenAlex
W4296782979
Cited by
85
References
3
Citations by year
2026: 27 · 2025: 25 · 2024: 19 · 2023: 14
FWCI
5.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • the Sci-Tech Key Program of the Guangzhou City Science Foundation (201802020001)
  • The Guangdong Innovative and Entrepreneurial Research Team Program (2016ZT06S638)
  • The Guangdong Province Sci-Tech International Key Program (2021A0505030027)
  • National Natural Science Foundation of China (81572982, 81773051, 81773256, 81902905, 81972692, 81972874)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
STING signaling, regulatory T cells, cervical cancer, tumor microenvironment, tumor-derived exosomes, TBK1-IRF3 signaling, Smad3 phosphorylation, STAT5 phosphorylation, immunosuppression, CCL22, CD8+ T cells, T cell receptor signaling
MeSH terms
STING Protein, Animals, Uterine Cervical Neoplasms, DNA, Female, Humans, Immunosuppression Therapy, Interferons, Membrane Proteins, Transforming Growth Factors, Receptors, Interleukin-2, Transforming Growth Factor beta, Interferon-beta, T-Lymphocytes, Regulatory, STAT5 Transcription Factor, Mice, Forkhead Transcription Factors, Tumor Microenvironment

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