Project Grant R37CA288447

THE REGULATION OF GUT MACROPHAGE'S FUNCTION BY THE BILE ACID RECEPTOR FXR - PROJECT SUMMARY/ABSTRACT: COLITIS-ASSOCIATED COLORECTAL CANCER (CAC) IS ONE OF THE MOST DEADLY TYPES OF COLORECTAL CANCER (CRC) THAT CAUSES THE MOST MORBIDITY AND MORTALITY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASE (IBD). THE EARLY DETECTION OF DYSPLASTIC OR MALIGNANT LESIONS IN PATIENTS WITH ULCERATIVE COLITIS IS CHALLENGING, WHICH RESULTED IN DELAYED DIAGNOSIS AND LIMITED THERAPEUTIC EFFICACY OF CAC. BILE ACIDS (BAS), AS EARLY DIETARY SENSORS, ARE CRITICAL MEDIATORS OF GUT PHYSIOLOGY, PARTLY BY AFFECTING THEIR MASTER RECEPTOR, FARNESOID X RECEPTOR (FXR) 'S ACTIVITY. BAS OVERPRODUCTION IS IMPLICATED IN DIARRHEA ASSOCIATED WITH IBD AND CAC, WITH WHICH THE FUNCTION OF FXR IS SEVERELY COMPROMISED. THE BAS-FXR AXIS IS A CONVERGENT POINT OF GENETIC AND DIETARY RISK FACTORS OF CRC. IN ADDITION, FXR IS A CRUCIAL MODULATOR OF THE PRO-AND ANTI-INFLAMMATORY RESPONSES IN THE INTESTINAL EPITHELIUM. INTESTINAL MACROPHAGES CONSTITUTE THE LARGEST POOL OF MACROPHAGES IN THE BODY AND HAVE EMERGED AS CRUCIAL SENTINELS FOR GUT MICROBIOME AND METABOLITE RECOGNITION. HOWEVER, DUE TO THE EXCEPTIONAL PLASTICITY OF GUT MACROPHAGES DURING CANCER PROGRESSION, THERE IS A MAJOR LACK OF MECHANISTIC UNDERSTANDING OF HOW GUT MACROPHAGES SENSE BAS AND HOW FXR REGULATES GUT MACROPHAGES' FUNCTION, AND MEDIATE ITS INTERACTION WITH OTHER CELL TYPES IN CAC. OUR PRELIMINARY STUDIES REVEALED THAT EPITHELIUM DAMAGE AND INTESTINAL INFLAMMATION RESULTED IN THE LOSS OF BAS HOMEOSTASIS AND COMPROMISED FXR SIGNALING IN CAC MICE MODELS. OUR OVERARCHING HYPOTHESIS IS THE DYSREGULATED BAS-FXR AXIS FURTHER INDUCES PATHOLOGICAL IMMUNE LANDSCAPE CHANGES, ESPECIALLY IN MACROPHAGES, WHICH CROSSTALKED WITH TH17 CELLS, TOGETHER PROMOTING TUMORIGENESIS. THIS PROPOSAL AIMS TO EVALUATE THE MECHANISMS OF ACTION (MOA) OF FXR AGONISM INCLUDING FDA-APPROVED OBETICHOLIC ACID (OCA) ON GUT MACROPHAGES' DIFFERENTIATION AND FUNCTION IN VITRO AND IN VIVO, INCLUDING EXPANSION OF ANIMAL TESTING TO DELINEATE BREADTH OF THIS ANTI-CANCER EFFICACY ON BOTH COLITIS AND CAC, AS AN IMMUNOMODULATOR DRUG. THREE SPECIFIC AIMS WILL BE PURSUED: AIM 1 WILL INVESTIGATE THE IMPACT OF INFLAMMATION- AND TUMOR-INDUCED, HOST- AND MICROBIAL-DERIVED BAS ON MACROPHAGE AND ITS CROSSTALK TO T CELL AND INTESTINAL STEM CELLS. AIM 2 WILL INVESTIGATE THE GUT MACROPHGES' DEPENDENCE ON FXR IN MODULATING ITS FUNCTION IN CAC MICE MODEL. AIM3 OF THIS PROPOSAL WILL DETERMINE THE THERAPEUTIC UTILITY OF ACTIVATION OF FXR IN GUT MACROPHAGE FOR THE TREATMENT OF CAC. BESIDES, WE WILL ALSO VALIDATE THE COMBINATION THERAPIES TO MAXIMIZE THE EFFICACY OF CANCER TREATMENTS INCLUDING RATIONAL COMBINATIONS OF ANTI-IL23 AND FXR AGONISTS. WE BELIEVE INVESTIGATING THE ROLE OF THE BAS-FXR AXIS IN INFLAMMATION-INDUCED AND TUMOR-INFILTRATED MACROPHAGES WILL FACILITATE OUR UNDERSTANDING OF THE ETIOLOGY OF COLITIS- INDUCED COLON CANCER. THE PROPOSED STUDY OF FXR LIGANDS WILL HASTEN THE DEVELOPMENT OF NOVEL THERAPEUTICS FOR THIS DEBILITATING AND MOST LETHAL COLORECTAL CANCER.