Abstract 5395: The influence of hyperthermia on epigenetic signaling in dysbiotic tumor vasculature

Abstract The overall use of antibiotics has increased significantly in recent years. Although they resolve infections, oral antibiotics (ABX) severely alter the gut microbiota, disrupting commensal bacteria crucial for maintenance of various homeostatic processes. ABX-induced microbial imbalance, or dysbiosis, has systemic and long-lasting deleterious effects on the host. For example, we and others have shown that distal, non-GI tract solid tumors show accelerated progression during dysbiosis due to vascular immune suppression. Localized hyperthermia has been increasingly recognized to elicit various cellular responses, yet the epigenetic effects of hyperthermia on the tumor vasculature during ABX-induced dysbiosis are unknown. The balance of histone acetylation and deacetylation plays a critical role in the regulation of gene expression and thereby cellular processes. Therefore, we assessed which histone deacetylases (HDACs) are expressed and their abundance in endothelial cells of various sources with or without dysbiotic stress and/or hyperthermia to understand the utility of thermal medicine to promote normal functioning of the vasculature in dysbiotic patients. We found that HDAC expression levels differed among endothelial origins and that hyperthermia (60 min of either 41.5 °C or 43 °C) influenced the HDAC levels differentially. Especially HDAC 2, 3 and 8 were inhibited by hyperthermia. Additionally, we found that the vasculature receptors for endogenous HDAC inhibitors, GPR41, GPR43, and GPR109a are less abundant intrinsically on dysbiotic than orthobiotic tumor endothelial cells and that hyperthermia increased this expression. Although further studies are warranted, these results demonstrate that hyperthermia exerts epigenetic effects and is capable of overcoming the dysbiosis-induced phenotype. Since anti-cancer treatment with HDAC inhibitors has shown promise in the clinic but is hindered by systemic toxicities, localized hyperthermia may become a viable alternative in the future. Citation Format: Hailey Kristian, Samir Jenkins, Robert Griffin, Ruud Petrus Dings. The influence of hyperthermia on epigenetic signaling in dysbiotic tumor vasculature [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(6_Suppl):Abstract nr 5395.