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

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-gamma) 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.