PROJECT SUMMARY African-American men (AAM) are known to present with more advanced disease resulting from both biological and socio-economic factors. Specific to biological factors, there is emerging data suggesting that AAM with prostate cancer (PCa) have an immunosuppressive tumor immune microenvironment (TIME) characterized by low DNA damage repair and high IFN-response pathway. Consequently, immune mediators and DNA damage response may play a major role in PCa biology in AAM. The mechanism and potential therapeutic benefit of combining immune modulators to disrupt the TIME for therapeutic gain in AAM with PCa is an area of active investigation. Furthermore, whether immune-modulatory therapy has differential effects on immune cell-types within the TIME of AAM vs. European-American men (EAM) is currently unknown. The proposed studies in this application will first computationally deconvolute the TIME of AAM and EAM highlighting the functional characteristics of key immune cells and soluble immune mediators. To overcome the limitation of cell line models, we will use a novel bioengineered platform to study tumor-immune interactions and mechanistically define how differences in the STING-IFN response pathway impacts response and/or resistance to immune modulators. Next, we will evaluate how differences in the TIME from AAM and EAM may affect the therapeutic response to immune-modulators using patient-derived explants – a unique ex-vivo model from fresh viable surgical specimens. Importantly, we will also validate these results in serial patient-derived biopsies and blood samples that have been collected as part of a phase II clinical study combining ADT, RT and immunotherapy (NCT03543189). These studies will unravel mechanisms that can be exploited to identify new therapeutic approaches to improve outcomes in AAM with PCa.