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Inhibition of PARP11 inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies.

ABSTRACT: Tumor-infiltrating regulatory T cells (TI-Tregs) elicit immunosuppressive effects in the tumor microenviroment (TME) leading to accelerated tumor growth and resistance to immunotherapies against solid tumors. Here we demonstrate that Poly-(ADP-ribose)-polymerase-11 (PARP11) acts as an essential regulator of TI-Tregs regulatory and protumorigenic activities. Expression of PARP11 correlated with TI-Treg infiltration and poor responses to immune checkpoint blockade (ICB) in human cancer patients. PARP11 was induced in the TI-Treg cells by tumor-derived factors including adenosine and prostaglandin E2. Knockout of PARP11 in the cells of the TME or treatment of tumor-bearing mice with selective PARP11 inhibitor ITK7 inactivated TI-Treg cells and reinvigorated anti-tumor immune responses. Accordingly, ITK7 decelerated tumor growth and significantly increased the efficacy of anti-tumor immunotherapies including ICB and adoptive transfer of CAR T cells. These results characterize PARP11 as a key driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE249299 | GEO | 2023/12/07

REPOSITORIES: GEO

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