Defining the Mechanistic Basis of Bacterial Androgen Production in Dampening Anti-Tumor Immunity and Promoting Resistance to Androgen Receptor Axis-Targeted Therapies for Metastatic Prostate Cancer

Project Summary/Abstract There is increasing evidence over the past decade that the composition of the gut microbiome is important for cancer therapy effectiveness including chemotherapy, endocrine therapy, and immune therapy. In fact, modulation of the microbiome is in clinical trials to enhance immunotherapy clinical responses in multiple solid tumors. Despite the explosion of studies on the microbiome-cancer therapy axis, relatively little is known about the mechanism(s) utilized by gut microbiota to shape therapy response or resistance. In metastatic castration resistant prostate cancer (mCRPC), the deadly form of the disease, intra-tumoral androgens likely mediate immunotherapy and endocrine therapy resistance. Collectively, the three PIs of this application have 1) identified and characterized the only known human-associated bacterial genes capable of converting glucocorticoids into non-conventional androgens; 2) collected and sequenced a 5-year microbiome biorepository from individuals with advanced prostate cancer taking oral androgen axis-targeted therapy; and 3) demonstrated that response to immunotherapy in advanced prostate cancer requires androgen receptor inhibition on T cells. Working together, we provide evidence that species of the gut microbiome produce androgen metabolites that act as ligands for the androgen receptor. This observation underscores our clinical observation that the gut microbiome of endocrine therapy or immunotherapy sensitive versus resistant patients is distinct and significantly unique. We propose that androgen metabolism by the gastrointestinal (GI) microbiota serves as a unique source of tumor-associated androgens that promote endocrine and immune therapy resistance. We propose the following aims: Aim 1: Define the functional significance of microbial-derived androgens on immunotherapy effectiveness. We will determine if microbial-derived androgens are sufficient to mediate therapy resistance and how these metabolites regulate murine and human T cell function. Aim 2: Determine the GI microbial gene pathways and androgen metabolites that are determinants of therapeutic response and resistance in mCRPC. These studies will identify novel bacterial species and genes associated with endocrine and immunotherapy resistance. Aim 3: Evaluate the impact of microbial-derived androgen production on tumor intrinsic growth, MHC I expression, and abiraterone acetate/prednisone resistance. We will evaluate the cause-and-effect relationship between microbial metabolism of androgens and endocrine therapy resistance. Cumulatively, these studies provide a mechanistic understanding of how the human microbiome promotes endocrine resistance and inhibits anti-tumor immunity and provide novel microbiota-associated therapeutic targets to reduce androgen-mediated immune suppression.