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Impact of SOCS1 inactivation on Marilyn adoptive cell transfer in MB49 female C57BL/6 bearing mice

ABSTRACT: In vivo, the expansion of antigen experienced CD4+ T cells is limited by intrinsic factors. Using an in vivo genome-wide CRISPR-Cas9 screen, we identified SOCS1 as a major non-redundant checkpoint imposing a brake on antigen experienced CD4+ T-cell proliferation upon antigen challenge. Although SOCS1 has been previously described as an inhibitor of CD8+ T-cell effector function, we highlight here that it is abrogating the CD4+ T-cell response. SOCS1 integrates several cytokines receptor signals to actively silence TCR-induced polycytokine signaling pathways, restraining CD4+ T cell proliferation and functions. Targeting SOCS1 in mouse and human CD4+ and CD8+ T cells improved the therapeutic efficacy of antitumor adoptive T-cell therapies, enhancing intra-tumor T cell accumulation, persistence and effector functions. SOCS1 deletion in CAR-T cells enhances CD4+ CAR T-cell proliferation/survival and polyfunctionality in vivo, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of re-stimulated CD4+ T cells, opening new possibilities to optimize adoptive T cell therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE154791 | GEO | 2021/09/02

REPOSITORIES: GEO

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