Abstract A076: Mono-ADT-ribosylation as a driver of the immunosuppressive tumor microenvironment

Abstract The immunosuppressive tumor microenvironment (TME) of solid tumors is central to their ability to escape from immune surveillance and to resist anti-cancer therapies, including immunotherapies utilizing immune checkpoint blockade (ICB) and adoptive cell transfer therapy (ACT). Within the TME, redundant cellular and acellular factors attenuate anti-tumor immune responses. These factors, including adenosine, prostaglandin E2, immunosuppressive myeloid cells, and regulatory T (Treg) cells, suppress the anti-tumor CD8+ cytotoxic T lymphocytes (CTLs) and confer resistance to immune therapies. Inactivation of the type I interferon (IFN1) pathway in the immune cells represents a key mechanism by which CTLs are inactivated, yet tumor-infiltrating Treg cells (TI-Tregs) are enabled to elicit immunosuppressive effects. Two PARP members catalyzing the transfer of mono-(ADP-ribose), PARP7 and PARP11 are involved in this inactivation via suppression of IFN1 production and acceleration of proteolytic degradation of the IFNAR1 receptor for IFN1. Here, we demonstrate that PARP11 is a crucial regulator of the immunosuppressive TME. In the CTLs, PARP11 mediated their inactivation while acting as an essential regulator of TI-Tregs immunosuppressive functions and pro-tumorigenic activities. Expression of PARP11 correlated with TI-Treg infiltration and poor responses to 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 critical driver of TI-Treg activities and a major regulator of immunosuppressive TME and argue for targeting PARP11 to augment anti-cancer immunotherapies. Citation Format: Serge Y. Fuchs. Mono-ADT-ribosylation as a driver of the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A076.