Project Grant F31CA317331

DEFINING A REGULATORY ROLE FOR ANDROGEN RECEPTOR SIGNALING ON DENDRITIC CELL FUNCTION - PROJECT SUMMARY THERE IS GROWING EVIDENCE TO SUPPORT A ROLE FOR SEX HORMONE SIGNALING IN MODULATING SEX DIFFERENCES IN CANCERS, INCLUDING MELANOMA. IN PARTICULAR, ANDROGENS, WHICH DRIVE MALE SEX CHARACTERISTICS, HAVE BEEN SHOWN TO PROMOTE MELANOMA GROWTH AND REDUCE INFILTRATION OF IMMUNE CELLS. CONVENTIONAL DENDRITIC CELLS (CDCS) ARE A TYPE OF ANTIGEN PRESENTING CELL THAT PLAYS A CRITICAL ROLE IN ANTI-TUMOR IMMUNITY. RECENT WORK USING CASTRATED MICE HAS SUGGESTED THAT ANDROGENS MAY REDUCE CDC MATURATION. HOWEVER, THE MECHANISMS BY WHICH ANDROGENS REGULATE CDCS AND THEIR ANTI-TUMOR FUNCTIONS REMAIN UNKNOWN. TO DIRECTLY INTERROGATE THE ROLE ANDROGEN SIGNALING PLAYS IN CDC FUNCTION, WE DEVELOPED A NOVEL MOUSE MODEL WHICH HAS A CDC-SPECIFIC ANDROGEN RECEPTOR (AR) DELETION. USING THIS MODEL, WE FOUND THAT CDC CELL-INTRINSIC AR SIGNALING DECREASED CDC MATURATION AND T CELL ACTIVATION IN MELANOMA. WE FOUND THAT UPON GENETIC DELETION OR PHARMACOLOGICAL INHIBITION OF AR, CDCS SIGNIFICANTLY INCREASED TUMOR ANTIGEN PHAGOCYTOSIS AND EXPRESSION OF ANTIGEN PRESENTATION MOLECULES. IMPORTANTLY, ANIMALS LACKING AR SIGNALING IN CDCS SHOWED SIGNIFICANTLY IMPROVED T CELL-MEDIATED CONTROL OF MELANOMA TUMOR GROWTH COMPARED TO AR-PROFICIENT CONTROLS. THESE FINDINGS SUGGEST AR SIGNALING SUPPRESSES CDC MATURATION AND ANTIGEN PRESENTATION, LIMITING ANTI-TUMOR T CELL RESPONSES. THEREFORE, I HYPOTHESIZE THAT ANDROGEN RECEPTOR (AR) SIGNALING TRANSCRIPTIONALLY REPRESSES CDC MATURATION AND ANTIGEN PRESENTATION, RESULTING IN REDUCED CD8+ T CELL PRIMING AND LESS EFFECTIVE ANTI-TUMOR IMMUNE RESPONSES. TO INVESTIGATE THE MECHANISMS BEHIND AR REGULATION OF CDCS, I WILL UTILIZE GENETIC TECHNIQUES AND FLUORESCENT PROTEIN AND TUMOR MODEL SYSTEMS TO DETERMINE PATHWAYS THAT LEAD TO DEFECTIVE CDC-MEDIATED ANTI-TUMOR RESPONSES. THIS PROPOSAL AIMS TO: 1) DEFINE THE IMPACT OF CELL-INTRINSIC AR SIGNALING ON CDC-MEDIATED ANTIGEN PROCESSING AND THE GENERATION OF ANTIGEN- SPECIFIC CD8+ T CELL RESPONSES AND 2) DETERMINE THE DIRECT TRANSCRIPTIONAL INTERACTIONS OF AR WITHIN CDCS. EXPLORING THESE CRITICAL PATHWAYS THAT ENHANCE INTERACTION AND COMMUNICATION BETWEEN CDCS AND T CELLS HAS THE POTENTIAL TO INTRODUCE IMPROVED THERAPEUTIC STRATEGIES FOR CANCER TREATMENT. UNDERSTANDING HOW SEX HORMONES, AND IN PARTICULAR ANDROGENS, IMPACT CANCER IMMUNITY WILL PAVE THE WAY FOR DEVELOPING TAILORED STRATEGIES BASED ON SEX-SPECIFIC IMMUNE RESPONSES.