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

Autor:	Benoit-Lizon I; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Jacquin E; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France.; INSERM, UMR-S 1193, Université Paris-Saclay, Châtenay-Malabry, France., Rivera Vargas T; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Richard C; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Roussey A; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Dal Zuffo L; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Martin T; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Melis A; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Vinokurova D; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Shahoei SH; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France.; Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, IL, USA., Baeza Garcia A; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Pignol C; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France., Giorgiutti S; INSERM UMR - S1109, Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France., Carapito R; Laboratoire d'ImmunoRhumatologie Moléculaire, GENOMAX platform, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Strasbourg, France., Boidot R; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France.; Department of Biology and Pathology of Tumors, Centre Georges François Leclerc, Dijon, France., Végran F; INSERM, U1231, Dijon, France.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France.; Department of Biology and Pathology of Tumors, Centre Georges François Leclerc, Dijon, France., Flavell RA; Department of Immunobiology, Yale University School of Medicine, New Heaven, CT, USA., Ryffel B; UMR 7355, Experimental and Molecular Immunology and Neurogenetics, CNRS, Orléans, France.; Department of Immunology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa., Nelson ER; Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, IL, USA.; Anticancer Discovery from Pets to People Theme, University of Illinois Urbana-Champaign, Cancer Center at Illinois, Urbana Champaign, Illinois, USA.; University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, IL, USA., Soulas-Sprauel P; INSERM UMR-S1109, Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Faculty of Pharmacy, Université de Strasbourg, Strasbourg, France., Lawrence T; Centre d'Immunologie de Marseille-Luminy, Université Aix-Marseille, INSERM, CNRS, Marseille, France., Apetoh L; INSERM, U1231, Dijon, France lionel.apetoh@inserm.fr.; UFR Sciences de Santé, Université Bourgogne Franche-Comté, Dijon, France.; INSERM, U1100, Tours, France.; Faculté de Médecine, Université de Tours, Tours, France.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2022 Jan; Vol. 10 (1).
DOI:	10.1136/jitc-2021-003459
Abstrakt:	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. Competing Interests: Competing interests: LA performed consultancy work for Roche, Merck, Bristol-Myers Squibb, and Orega Biotech and was a recipient of a research grant from Sanofi. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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