CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of T H 1 and T H 9 cells
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. Here, we tested whether STING activation modulated the effector fu...
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Published in | Journal for immunotherapy of cancer Vol. 10; no. 1; p. e003459 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
BMJ Publishing Group
01.01.2022
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Subjects | |
Online Access | Get full text |
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Summary: | 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.
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
9 cell antitumor activity against mouse melanoma upon adoptive transfer.
We found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of T
1 and T
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
1 cell differentiation. However, STING activation favors T
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
1 and T
9-derived cytokines, and STING activation enhances the antitumor activity of T
9 cells upon adoptive transfer.
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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Bibliography: | PMCID: PMC8804688 |
ISSN: | 2051-1426 2051-1426 |
DOI: | 10.1136/jitc-2021-003459 |