Abstract 3144: Selective HDAC10 inhibitor enhances innate antitumor immunity

Abstract Most anticancer therapies aim to target specific mechanisms that regulate or potentially inhibit the proliferation and survival of cancer cells. Macrophages play a crucial role in the tumor microenvironment (TME), exhibiting both pro and antitumoral functions depending on the polarization state. Our lab focuses on transforming the immune suppressive TME into an antitumoral environment, explicitly enhancing the proinflammatory M1 macrophage phenotype using HDAC inhibitors. Many research studies have shown the aberrant expression of HDAC10 in cancer and various pathologies. However, the deacetylation targets and biological functions of HDAC10 remain poorly characterized due to a lack of specific and potent HDAC10 inhibitors with cellular activity. HDAC10 has a unique structure and substrate preference. Understanding its mechanisms of action is crucial for developing effective therapies. In our study to identify the potential HDAC10-specific inhibitor, we screened 13 HDAC10 inhibitors for their ability to suppress the M2 macrophage phenotype. We also identified six potent inhibitors that suppress the M2 phenotype and tested for cytotoxicity and HDAC inhibition. Interestingly, FM60 with 0.9 nM IC50 against HDAC10 in cells showed negligible cytotoxicity and more than 60 % HDAC inhibition. Inhibition of HDAC10 in primary mouse bone marrow-derived macrophages results in upregulating proinflammatory M1 markers-iNOS and TNFa while concurrently downregulating the expression of anti-inflammatory M2 markers Arginase1 and Fizz1. Flow cytometry analysis demonstrated reduced CD206 + and increased CD80 + macrophages in BMDMs treated with FM60, indicating potential antitumor effects. M1-like macrophages are antitumoral due to their intrinsic phagocytosis and antigen presentation capability. To investigate the phagocytic potential of FM60, BMDMs from GFP mice were left unpolarized (M0) or polarized to M1, pretreated with HDAC10i FM60, and co-cultured with cell trace far red stained SM1 murine melanoma cells. Images captured at every 20-minute interval demonstrated a significant increase in phagocytosis by M1 macrophages treated with FM60. Principal Component Analysis (PCA) showed the closest association between BMDMs from HDAC10 KO mice and FM60-treated in M1 macrophage phenotype, additionally, RNA seq analysis indicated that treatment with FM60 significantly regulates polyamine biosynthesis, crucial for tumorigenesis. To evaluate the antitumor immunity in syngeneic murine melanoma, FM60 was given intraperitoneally at varying doses. 50 mg/kg body weight of FM60 significantly reduced the tumor growth, enhancing its antitumor effects. These findings provide the rationale for using HDAC10is as an immunotherapeutic anticancer agent. Citation Format: Nithya Gajendran, David Quiceno-Torress, Xintang Li, Bryan Weselman, Manasa Suresh, Sonia Sebaoui, Fereshteh Mahmoudi, Marie Durr, Satish Kumar Reddy Noonepalle, Wolfgang Sippl, Alejandro Villagra. Selective HDAC10 inhibitor enhances innate antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3144.