Abstract 3733: Gut microbiota-dependent bile acidtaurodeoxycholic acid, TDCAfacilitates anti-tumor immune responses by modulating cytotoxic CD8 T cell immunity

Abstract

Abstract Gut microbiota are critical for effective immune checkpoint blockade therapy (ICT) for cancer. However, the underlying mechanisms by which gut microbiota and/or microbiota-derived metabolites augment antitumor response are largely unknown. Here, we utilized a preclinical melanoma (B16-F10) model and treated groups of mice (Jackson, C57BL/6J, female, 6-8 wks, n=14-26 per group) with seven distinct antibiotic treatments to induce unique gut microbiomes and metabolomes. Mice were then treated with ICT (anti-PD-1 and anti-CTLA-4), resulting in markedly heterogeneous tumor phenotypes (tumor volume and weight) as dictated by the specific antibiotic treatment. Using machine learning (e.g. random forest classifier), we identified metabolite candidates most strongly associated with ICT response (i.e. tumor volume and weight).One metabolite candidate, the bile acid taurodeoxycholic acid, TDCA, had previously been identified by my group as associated with anti-PD-1/anti-CTLA-4 response in human melanoma patients (PMID 28923537). Administration of TDCA alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness in mice. Utilizing both in vitro/ex vivo immune cell assays and in vivo preclinical models, we have validated that TDCA treatment directly boosted the antitumor cytotoxic CD8+ T cell responses (i.e. IFN-gamma production, anti-tumor cytotoxicity, tumor growth, etc.) without affecting innate immune responses. Bulk RNAseq of CD8 T cell analysis indicated that TDCA modulate CD8 T cell function through IFN pathway. Together, our findings suggest that the gut microbial metabolite TDCA could promote immunotherapy efficacy through regulation of CD8+ T cell immunity and has the potential to be utilized as a novel therapeutic agent to enhance ICT efficacy. Citation Format: Wenng li, Hesuiyuan Wang, Laura Coughlin, Nicole Poulides, Priscilla Del Valle, Jake Lichterman, Xiaowei Zhan, Chen Liao, Suzette N. Palmer, Xin Li, Andrew Y. Koh. Gut microbiota-dependent bile acidtaurodeoxycholic acid, TDCAfacilitates anti-tumor immune responses by modulating cytotoxic CD8 T cell immunity [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 3733.