Abstract 1122: Inhibition of HDAC6 enhanced radiation therapy induced antitumor response in melanoma

Abstract Patients with advanced melanoma are often treated with radiation therapy (RT) in combination with immunotherapies. Immunogenic tumor cell death induced by radiation is known to activate innate and adaptive immunity. Macrophage activity in the irradiated tumor microenvironment (TME) has been implicated to play a critical role in post-RT innate immune responses. However, tumor-associated macrophages (TAMs) due to their phenotypic plasticity convert from initial antitumor M1 phenotype to protumor M2 macrophages resulting in relapse and metastasis of any surviving tumor cells. Therefore, strategies regulating tumor macrophages post-radiation can enhance the therapeutic effectiveness of radiation therapy. Here, we report targeting HDAC6 function with a novel selective inhibitor (SP-2-225) as a potential therapeutic candidate for combination with RT. When administered intraperitoneally at a dose of 25mg/kg, SP-2-225 resulted in significant tumor suppression in the immunocompetent SM1 murine melanoma model. Phenotyping of tumor immune infiltrate indicated a profound decrease in M2 macrophages resulting in an M1/M2 macrophage ratio and an increase in CD8 effector memory T-cells. Further, in-vitro co-culture studies using trans-well assays indicated that irradiated tumor cells attract M2 macrophages, and treatment with SP-2-225 abrogated the M2 macrophage migration but did not alter M1 macrophage migration. In addition, 24 hours post-RT, intratumor administration of SP-2-225 treated M1 macrophages as adoptive cell therapy resulted in diminished tumor growth. The combination of conditioned M1 macrophages with an irradiated tumor microenvironment resulted in an increased M1/M2 ratio and infiltration of effector memory and central memory CD8 T-cells underscoring the influence of transplanted macrophages on the local antitumor immunity. Therefore, our findings demonstrate the ability of HDAC6 inhibitors to regulate macrophage function and phenotype as a cell therapy for use in combination with radiation therapy. Citation Format: Xintang Li, Manasa Suresh, Hawa Coulibaly, David Quiceno-Torres, Nithya Gajendran, Karen Tan, Satish Noonepalle, Scott Grindrod, Anatoly Dritschilo, Alejandro Villagra. Inhibition of HDAC6 enhanced radiation therapy induced antitumor response in melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1122.