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Cited by 85interferon and immune responsesImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of T H 1 and T H 9 cells

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Benoit-Lizon, Isis, Jacquin, Elise, Rivera Vargas, Thaiz, Richard, Corentin, Roussey, Aurélie, Dal Zuffo, Ludivine, Martin, Tiffany, Melis, Andréa +14 more·2022·Journal for ImmunoTherapy of Cancer
DOI 10.1136/jitc-2021-003459PMC PMC8804688
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Abstract

Background: While stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive. Methods: Here, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances T H 9 cell antitumor activity against mouse melanoma upon adoptive transfer. Results: We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of T H 1 and T H 9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of T H 1 cell differentiation. However, STING activation favors T H 9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on T H 1 and T H 9-derived cytokines, and STING activation enhances the antitumor activity of T H 9 cells upon adoptive transfer. Conclusion: Our results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.

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  • Recent studies have indicated that STING agonist-induced T cell death depends on the type and doses of STING agonists.

    “Although it was proposed that STING agonist can induce T cell death through the activation of proapoptotic transcriptional programs58, recent studies have indicated that this effect depends on the type and doses of STING agonists59,60.”

    From Epigenetic state determines the in vivo efficacy of STING agonist therapy (2023) · cites this paper as [60]

  • Two recent reports have shown that T cell-intrinsic STING signaling could control differentiation and effector functions of CD8+ and CD4+ T cells.

    “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 [60]

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Authors
Benoit-Lizon, I., Jacquin, E., Rivera Vargas, T., Richard, C., Roussey, A., Dal Zuffo, L., Martin, T., Melis, A., Vinokurova, D., Shahoei, S. H., Baeza Garcia, A., Pignol, C., Giorgiutti, S., Carapito, R., Boidot, R., Végran, F., Flavell, R. A., Ryffel, B., Nelson, E. R., Soulas-Sprauel, P., Lawrence, T., & Apetoh, L.
Affiliations
  • Inserm (FR)
  • INSERM, U1231, Dijon, France
  • Yale University (US)
  • Centre National de la Recherche Scientifique (FR)
  • Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, IL, USA
ORCID
Venue
Journal for ImmunoTherapy of Cancer
Publisher
BMJ
Published
2022-01
Volume
10
Issue
1
Pages
e003459
ISSN
2051-1426 (ISSN-L)
DOI
10.1136/jitc-2021-003459
PMC
PMC8804688
OpenAlex
W4210334002
Cited by
85
References
10
Citations by year
2026: 18 · 2025: 29 · 2024: 16 · 2023: 13 · 2022: 9
FWCI
6.40
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, other-oa)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Cancer Institute of the National Institutes of Health (R01CA234025)
  • Department of Defense (BC171214)
  • Fondation pour la Recherche Médicale (ARF20170938687)
  • European Research Council (677251)
  • Fondation ARC (DOC20190509200)
  • FEDER
  • ANR (19-CE15-0028-01)
  • LabEX MabImprove
  • Agence Nationale de la Recherche (ANR-11-LABX-0021, ANR-14-CE14-0026-04)
  • Fondation de France
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
STING signaling, CD4+ T cells, Th1 cells, Th9 cells, cGAMP, antitumor immunity, tumor-infiltrating T cells, interferon-gamma, IL-9, IRF3, type I interferon receptor, mTOR signaling, melanoma, adoptive T cell therapy, T cell differentiation
MeSH terms
STING Protein, Animals, Cell Differentiation, Female, Membrane Proteins, Mice, Inbred C57BL, Nucleotides, Cyclic, Signal Transduction, CD4-Positive T-Lymphocytes, Interleukin-9, Th1 Cells, Interferon Regulatory Factor-3, Mice, TOR Serine-Threonine Kinases

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