PMID- 35091453
OWN - NLM
STAT- MEDLINE
DCOM- 20220323
LR  - 20220405
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 10
IP  - 1
DP  - 2022 Jan
TI  - CD4 T cell-intrinsic STING signaling controls the differentiation and effector 
      functions of T(H)1 and T(H)9 cells.
LID - 10.1136/jitc-2021-003459 [doi]
LID - e003459
AB  - 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.
CI  - (c) Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published 
      by BMJ.
FAU - Benoit-Lizon, Isis
AU  - Benoit-Lizon I
AUID- ORCID: 0000-0003-1187-6828
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Jacquin, Elise
AU  - Jacquin E
AUID- ORCID: 0000-0003-0368-4113
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
AD  - INSERM, UMR-S 1193, Universite Paris-Saclay, Chatenay-Malabry, France.
FAU - Rivera Vargas, Thaiz
AU  - Rivera Vargas T
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Richard, Corentin
AU  - Richard C
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Roussey, Aurelie
AU  - Roussey A
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Dal Zuffo, Ludivine
AU  - Dal Zuffo L
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Martin, Tiffany
AU  - Martin T
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Melis, Andrea
AU  - Melis A
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Vinokurova, Daria
AU  - Vinokurova D
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Shahoei, Sayyed Hamed
AU  - Shahoei SH
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
AD  - Department of Molecular and Integrative Physiology, University of Illinois at 
      Urbana Champaign, Urbana, IL, USA.
FAU - Baeza Garcia, Alvaro
AU  - Baeza Garcia A
AUID- ORCID: 0000-0001-6032-7847
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Pignol, Cassandre
AU  - Pignol C
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
FAU - Giorgiutti, Stephane
AU  - Giorgiutti S
AD  - INSERM UMR - S1109, Department of Clinical Immunology and Internal Medicine, 
      National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary 
      Center for Primary Immunodeficiency, Hopitaux Universitaires de Strasbourg, 
      Universite de Strasbourg, Strasbourg, France.
FAU - Carapito, Raphael
AU  - Carapito R
AD  - Laboratoire d'ImmunoRhumatologie Moleculaire, GENOMAX platform, INSERM UMR_S 
      1109, Faculte de Medecine, Federation Hospitalo-Universitaire OMICARE, Federation 
      de Medecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, 
      Strasbourg, France.
FAU - Boidot, Romain
AU  - Boidot R
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
AD  - Department of Biology and Pathology of Tumors, Centre Georges Francois Leclerc, 
      Dijon, France.
FAU - Vegran, Frederique
AU  - Vegran F
AD  - INSERM, U1231, Dijon, France.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
AD  - Department of Biology and Pathology of Tumors, Centre Georges Francois Leclerc, 
      Dijon, France.
FAU - Flavell, Richard A
AU  - Flavell RA
AD  - Department of Immunobiology, Yale University School of Medicine, New Heaven, CT, 
      USA.
FAU - Ryffel, Bernhard
AU  - Ryffel B
AD  - UMR 7355, Experimental and Molecular Immunology and Neurogenetics, CNRS, Orleans, 
      France.
AD  - Department of Immunology, Institute of Infectious Disease and Molecular Medicine, 
      University of Cape Town, Cape Town, South Africa.
FAU - Nelson, Eric R
AU  - Nelson ER
AD  - Department of Molecular and Integrative Physiology, University of Illinois at 
      Urbana Champaign, Urbana, IL, USA.
AD  - Anticancer Discovery from Pets to People Theme, University of Illinois 
      Urbana-Champaign, Cancer Center at Illinois, Urbana Champaign, Illinois, USA.
AD  - University of Illinois Cancer Center, University of Illinois at Chicago, Chicago, 
      IL, USA.
FAU - Soulas-Sprauel, Pauline
AU  - Soulas-Sprauel P
AD  - 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, Universite de 
      Strasbourg, Strasbourg, France.
FAU - Lawrence, Toby
AU  - Lawrence T
AD  - Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, INSERM, CNRS, 
      Marseille, France.
FAU - Apetoh, Lionel
AU  - Apetoh L
AUID- ORCID: 0000-0002-2774-438X
AD  - INSERM, U1231, Dijon, France lionel.apetoh@inserm.fr.
AD  - UFR Sciences de Sante, Universite Bourgogne Franche-Comte, Dijon, France.
AD  - INSERM, U1100, Tours, France.
AD  - Faculte de Medecine, Universite de Tours, Tours, France.
LA  - eng
GR  - 677251/ERC_/European Research Council/International
GR  - R01 CA234025/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
RN  - 0 (Interferon Regulatory Factor-3)
RN  - 0 (Interleukin-9)
RN  - 0 (Irf3 protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (Nucleotides, Cyclic)
RN  - 0 (Sting1 protein, mouse)
RN  - 0 (cyclic guanosine monophosphate-adenosine monophosphate)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/cytology/*immunology
MH  - Cell Differentiation
MH  - Female
MH  - Interferon Regulatory Factor-3/physiology
MH  - Interleukin-9/*physiology
MH  - Membrane Proteins/*physiology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Nucleotides, Cyclic/pharmacology
MH  - Signal Transduction/physiology
MH  - TOR Serine-Threonine Kinases/physiology
MH  - Th1 Cells/cytology/*immunology
PMC - PMC8804688
OTO - NOTNLM
OT  - CD4-positive T lymphocytes
OT  - adaptive immunity
OT  - immunomodulation
OT  - melanoma
COIS- 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.
EDAT- 2022/01/30 06:00
MHDA- 2022/03/24 06:00
PMCR- 2022/01/28
CRDT- 2022/01/29 05:43
PHST- 2021/12/02 00:00 [accepted]
PHST- 2022/01/29 05:43 [entrez]
PHST- 2022/01/30 06:00 [pubmed]
PHST- 2022/03/24 06:00 [medline]
PHST- 2022/01/28 00:00 [pmc-release]
AID - jitc-2021-003459 [pii]
AID - 10.1136/jitc-2021-003459 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2022 Jan;10(1):e003459. doi: 10.1136/jitc-2021-003459.