6533b7d3fe1ef96bd125fd73

RESEARCH PRODUCT

Etude du rôle de STING dans la biologie des lymphocytes T CD4 : application en immunothérapie anticancéreuse

subject

description

Recognition of danger signals by intracellular or extracellular receptors expressed by innate immune cells is crucial for the establishment of an effective adaptive immune response. STING (Stimulator of Interferon Genes) is a protein located in the endoplasmic reticulum discovered in 2008 as being essential for the detection of cytosolic DNAs and the establishment of antiviral immune response mediated by type I interferons (IFNs). The STING protein also plays a key role in spontaneous anti-tumor immune responses and the administration of STING ligands in tumor-bearing mice favors tumor growth control. These observations have been verified in clinical trials in patients with melanoma, illustrating the therapeutic potential of activating STING in cancer immunotherapy.However, the mechanisms explaining the antitumor efficacy of STING ligands remain unclear. In vivo, STING ligands lead to dendritic cell activation. Dendritic cells are then responsible for setting up the adaptive immune response. While cytotoxic CD8 T lymphocytes have strong anti-tumor properties, helper CD4 T lymphocytes are also essential for the establishment of an effective anti-tumor immune response. The STING signaling pathway has mainly been described in myeloid cells, however several studies have shown that STING signaling pathway is functional in T lymphocytes. However, the intrinsic role of STING on the effector and antitumor properties of CD4 T lymphocytes remains unclear.My work reveals that STING ligands respectively increase the secretion of IL-9 and IFN-γ by TH9 and TH1 lymphocytes, two CD4 T cell subsets ascribed with potent anti-tumor activity, in a STING-dependent manner. Mechanistically, I was able to establish that STING modulates the effector functions of these two subtypes through different mechanisms: an IRF3-IFN-β axis for TH1 cells and an IFN-β-independent but mTOR-dependent axis for TH9 cells. In vivo antitumor effects of the STING ligand 2'3'-cGAMP involves CD4 T cells as well as the specific effector cytokines of TH1 and TH9, IFN-γ and IL-9 respectively. Finally, in the context of passive adoptive transfer in melanoma-bearing animals, activation of STING increases the antitumor effects of TH9 cells. These data indicate a new intrinsic role for STING in the modulation of the differentiation of CD4 T lymphocytes and the development of the adaptive anti-tumor immune response.