CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of T<sub>H</sub>1 and T<sub>H</sub>9 cells - Aix-Marseille Université Accéder directement au contenu
Article Dans Une Revue Journal for Immunotherapy of Cancer Année : 2022

CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells

Lionel Apetoh
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Résumé

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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hal-03951994 , version 1 (23-01-2023)

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Isis Benoit-Lizon, Elise Jacquin, Thaiz Rivera Vargas, Corentin Richard, Aurélie Roussey, et al.. CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells. Journal for Immunotherapy of Cancer, 2022, 10, ⟨10.1136/jitc-2021-003459⟩. ⟨hal-03951994⟩
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