Abstract 3442: FXR mediates macrophage intrinsic responses to suppress colon cancer progression

Abstract

Abstract Bile acids (BAs) affect the intestinal environment by ensuring barrier integrity, regulating epithelium turnover, maintaining microbiota balance, and modulating the immune system. As a master regulator of BAs homeostasis and innate immunity, Farnesoid X Receptor (FXR), is severely compromised in inflammatory bowel disease (IBD) and colitis-associated colorectal carcinoma (CAC) patients. At the front line, gut macrophages react to the microbiota and metabolites that breach the epithelium. We aim to study the role of the BAs-FXR axis in macrophages. To dissect how inflammation drives tumorigenesis, we employed a classic mouse model of CAC, profiled BAs and cytokines, monitored tumorigenesis, and examined the function of macrophages and Th17 cells. Moreover, we investigated the potential of FexD, an FXR agonist, in ameliorating intestinal inflammation, thus inhibiting tumorigenesis. Further, we identified how macrophage intrinsic FXR senses the BAs abnormality and reshapes the gut macrophages in vivo and ex vivo. We also investigated the potential role of pro-inflammatory cytokines in stimulating intestinal stem cells (ISCs)’ stemness using mouse organoids. This study demonstrates that inflammation-induced epithelial abnormalities compromised FXR signaling and altered BAs profile in CAC. Gut macrophage intrinsic FXR senses the aberrant BAs, leading to the secretion of pro-inflammatory cytokines, which promotes ISCs’ proliferation. Notably, FexD reduced intestinal inflammation and tumorigenesis by suppressing pro-inflammatory responses in gut macrophages and Th17 cells. Mechanistically, FXR regulates gut macrophages' recruitment, polarization, maturation, and crosstalk with Th17 cells. In summary, we uncovered a novel role of FXR modulation of gut macrophages, highlighting the potential of FXR as a therapeutic target over biologicals for treating colon cancer. Citation Format: Ting Fu, Xingchen Dong. FXR mediates macrophage intrinsic responses to suppress colon cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3442.