Dissecting the immunological mechanisms associated with prostate cancer progression in African-American men and exploring epigenetics-based immune modulation for therapy

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Project Summary Prostate Cancer (PCa) is a leading cause of cancer-related deaths among men in the United States. Within the general population, African-Americans, who constitute a minority group suffers a higher burden of the disease compared to other racial groups. A number of factors have been postulated to contribute to this disparity including genetic make-up, specific somatic genomic alterations, socio-economic and behavioral factors. It is now well established that immune cells recruited to the tumor microenvironment play crucial roles in shaping tumor cell biology. An outstanding issue therefore is whether immunological factors also contribute to prostate cancer behavior and progression in African-American (AA) men compared to their Caucasian counterparts. This issue is particularly important in light of our recent preliminary findings which suggest that a number of cellular and molecular inhibitory mechanisms are more prominently installed in PCa specimens from AA patients relative to specimens from North-American Caucasian (NAC) patients. Thus, we hypothesized that the immunological landscape of PCa in AA men is distinct from their Caucasian counterparts and this shapes tumor progression. With respect to therapeutic interventions, durable treatments still remain challenging for advanced PCa where there has been little to no success with current immunotherapy strategies. Our recent findings that a bivalent BRD4 inhibitor appears to promote a reduction in tumor-associated inhibitory T cells in a mouse PCa model raise the exciting possibility that it may be a promising immunotherapeutic for PCa treatment. Given the more prominent presence of these inhibitory T cells in AA PCa specimens, we rationalize that the effects of this drug may be more profound and potentially more beneficial in this minority group. In this regard, the present project seeks to understand the immunological landscape, hence potential mechanisms that are associated with PCa progression in AA versus NAC men by employing an unbiased single cell transcriptomic analysis of tumor-associated immune cells and to investigate the effects of the BRD4 inhibitor on these immune cells as a potential epigenetics-based immunomodulatory drug. Our planned studies will therefore focus on two specific aims: (1) To dissect the transcriptional signature of immune cells in the tumors of African-American prostate cancer patients compared to their Caucasian counterparts. (2) To determine the immunomodulatory effects of a bivalent BRD4 inhibitor in locally advanced PCa of AA or NAC patient origin. Through these studies, we expect to identify immune signatures that may be unique and which could inform potential differential behavior of the disease in AA men. Importantly, by understanding any differential effects of BRD4 inhibition on tumor-associated immune cells between the two demographics, it could guide future studies exploring its clinical applicability for PCa treatment in either of these patient populations.