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

项目摘要 前列腺癌（PCa）是美国男性癌症相关死亡的主要原因。内 作为少数群体的非裔美国人的疾病负担更高 与其他种族相比。据推测，造成这种差异的因素有很多 包括遗传组成、特定的体细胞基因组改变、社会经济和行为因素。是 现在已经确定，招募到肿瘤微环境中的免疫细胞在塑造肿瘤微环境中起着至关重要的作用。 肿瘤细胞生物学因此，一个悬而未决的问题是，免疫因素是否也有助于前列腺 非裔美国人（AA）男性与白人男性相比的癌症行为和进展。 鉴于我们最近的初步调查结果表明， 细胞和分子抑制机制更突出地安装在PCa标本从AA 患者相对于北美高加索（NAC）患者的标本。因此，我们假设 AA男性中PCa免疫学景观与他们的高加索对应者不同， 肿瘤进展。关于治疗干预措施，持久的治疗仍然具有挑战性， 晚期前列腺癌，目前的免疫治疗策略几乎没有成功。我们最近 研究发现，二价BRD4抑制剂似乎可以促进肿瘤相关抑制性T细胞的减少， 小鼠前列腺癌模型提出了一种令人兴奋的可能性，即它可能是一种有前途的前列腺癌免疫原。 治疗考虑到这些抑制性T细胞在AA PCa标本中的更突出的存在，我们合理化了 这种药物的效果可能更深刻，对这一少数群体可能更有益。在这 在这方面，本项目旨在了解免疫景观，从而潜在的机制 与AA与NAC男性中PCa进展相关的基因， 肿瘤相关免疫细胞的转录组学分析，并研究BRD4抑制剂的作用 作为一种潜在的基于表观遗传学的免疫调节药物。我们计划的研究将 因此，重点关注两个具体目标： (1)剖析非洲裔美国人前列腺肿瘤中免疫细胞的转录特征 癌症患者与高加索人相比。 (2)为了确定二价BRD 4抑制剂在局部晚期PCa中的免疫调节作用， AA或NAC患者来源。 通过这些研究，我们希望确定可能是独特的免疫特征， AA男性疾病的潜在差异行为。重要的是，通过了解任何不同的影响， BRD4对肿瘤相关免疫细胞的抑制在两种人口统计学之间，它可以指导未来 探索其在这些患者人群中用于PCa治疗的临床适用性的研究。

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.