In vivo genome-wide CRISPR screens identify SOCS1 as intrinsic checkpoint of CD4+T H 1 cell response

Aurélien Sutra Del Galy, Silvia Menegatti, Jaime Fuentealba, Francesca Lucibello, Laetitia Perrin, Julie Helft, Aurélie Darbois, Michael Saitakis, Jimena Tosello, Derek Rookhuizen, Marc Deloger, Pierre Gestraud, Gérard Socié, Sebastian Amigorena, Olivier Lantz, Laurie Menger

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    41 Citations (Scopus)

    Résumé

    Although CD8+ T cells undergo autonomous clonal proliferation after antigen stimulation in vivo, the expansion of activated CD4+ T cells is limited by intrinsic factors that are poorly characterized. Using genome-wide CRISPR-Cas9 screens and an in vivo system modeling of antigen-experienced CD4+ T cell recruitment and proliferation during a localized immune response, we identified suppressor of cytokine signaling 1 (SOCS1) as a major nonredundant checkpoint imposing a brake on CD4+ T cell proliferation. Using anti-interleukin-2 receptor (IL-2R) blocking antibodies, interferon-γ receptor (IFN-γR) knockout mice, and transcriptomic analysis, we show that SOCS1 is a critical node integrating both IL-2 and IFN-γ signals to block multiple downstream signaling pathways abrogating CD4+ T helper 1 (TH1) cell response. Inactivation of SOCS1 in both murine and human CD4+ T cell antitumor adoptive therapies restored intratumor accumulation, proliferation/survival, persistence, and polyfunctionality and promoted rejection of established tumors. However, in CD8+ T cells, SOCS1 deletion did not affect the proliferation but rather improved survival and effector functions, which allowed for optimal therapeutic outcome when associated with SOCS1 inactivation in CD4+ T cells. Together, these findings identify SOCS1 as a major intracellular negative checkpoint of adoptive T cell response, opening new possibilities to optimize CAR-T cell therapy composition and efficacy.

    langue originaleAnglais
    Numéro d'articleeabe8219
    journalScience Immunology
    Volume6
    Numéro de publication66
    Les DOIs
    étatPublié - 24 déc. 2021

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