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

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 TH9 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 TH1 and TH9 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 TH1 cell differentiation. However, STING activation favors TH9 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 TH1 and TH9-derived cytokines, and STING activation enhances the antitumor activity of TH9 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.

• Authors: Isis Benoit-Lizon, Elise Jacquin, Thaiz Rivera Vargas, Corentin Richard, Aurélie Roussey, Ludivine Dal Zuffo, Tiffany Martin, Andréa Melis, Daria Vinokurova, Sayyed Hamed Shahoei, Alvaro Baeza Garcia, Cassandre Pignol, Stéphane Giorgiutti, Raphaël Carapito, Romain Boidot, Frédérique Végran, Richard A Flavell, Bernhard Ryffel, Eric R Nelson, Pauline Soulas-Sprauel, Toby Lawrence, Lionel Apetoh
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 10 Issue 1 (01 2022) ISSN: 2051-1426 [Electronic] England
• PMID: 35091453 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Chemical References

• Interferon Regulatory Factor-3
• Interleukin-9
• Irf3 protein, mouse
• Membrane Proteins
• Nucleotides, Cyclic
• Sting1 protein, mouse
• cyclic guanosine monophosphate-adenosine monophosphate
• mTOR protein, mouse
• TOR Serine-Threonine Kinases

Topics

• Animals
• CD4-Positive T-Lymphocytes (cytology, immunology)
• Cell Differentiation
• Female
• Interferon Regulatory Factor-3 (physiology)
• Interleukin-9 (physiology)
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred C57BL
• Nucleotides, Cyclic (pharmacology)
• Signal Transduction (physiology)
• TOR Serine-Threonine Kinases (physiology)
• Th1 Cells (cytology, immunology)