Abstract A013: Selective HDAC6 inhibition by SP-2-225 enhances the innate anti-tumor immune response after radiation exposure

Abstract

Abstract Circulating tumor DNA fragments and other antigens resulting from radiation therapy cause activation of the STING pathway and initiate an inflammatory anti-tumor immune response. However, when pro-inflammatory immune cells interact with the tumor microenvironment, they are rapidly converted to their anti-inflammatory, pro-tumor state associated with wound healing. HDAC6 presents an important target due to its role in immune regulatory processes involved in antitumor immune responses. We have shown that SP-2-225, a selective inhibitor of HDAC6, regulates macrophages to recognize, phagocyte, and present antigens to the adaptive immune system. Treatment with SP-2-225 enhances the production of cancer-associated antigens and macrophage antigen cross-presentation to T cells. Through a non-cytotoxic mechanism, SP-2-225 significantly reduced the tumor volume in syngeneic SM1 melanoma and 4T1 breast models. Tumor analysis from treated animals showed a shift in the M1/M2 ratio of the infiltrating macrophages as compared to controls, demonstrating that SP-2-225 caused a pro-inflammatory, antitumor shift in the macrophage equilibrium present in the tumor microenvironment. The putative mechanism was identified through adoptive cell therapy where macrophages from naive animals were harvested and treated ex-vivo with SP-2-225. Reimplantation of these SP-2-225 ex-vivo treated macrophages resulted in reduced tumor volumes when compared to both vehicle and untreated macrophage animal cohorts. We propose that this selective inhibitor of HDAC6 offers potential in combination with radiation therapy for cancer. Citation Format: Scott Grindrod, Satish Noonepalle, Xingtang Li, David Quiceno, Mira Jung, Anatoly Dritschilo, Alejandro Villagra. Selective HDAC6 inhibition by SP-2-225 enhances the innate anti-tumor immune response after radiation exposure [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A013.