Abstract A080: The immunological signatures of African American prostate cancer as biological determinants of disease disparity
Authors: Oseni Saheed O. , Bag Arup , Oluwatola Oluwaseyi , DeMars Natalie , Adeegbe Dennis 
Published: January 2023

Abstract
Background: Prostate cancer (PCa) is currently the second leading cause of cancer-related deaths among men in the United States. African American men suffer the highest incidence of disease morbidity and mortality compared to other racial groups. Although socio-economic, cultural, epidemiological, and genomic factors have been described to contribute to cancer health disparities in African American men, there is a knowledge gap regarding how the tumor immune landscape shapes aggressive disease patterns in this patient population, and whether their tumor microenvironment (TME) is amenable to immune modulation. This study aims to identify distinct and targetable immunosuppressive phenotypes and immunological signatures in prostate tumors of AA patients. Methodology: Peripheral blood from consented African American (AA) and Caucasian American (CA) patients undergoing prostatectomy at Moffitt Cancer Center were analyzed by Luminex multiplex cytokine/chemokine assay and comprehensive immune profiling via multi-parameter flow cytometry. Also, multiparameter immune profiling of freshly resected PCa specimens obtained from these same patients after prostatectomy was performed. In addition, multiplex immunohistochemical staining was performed on prostate tumor tissue microarrays to compare the proportions and phenotypes of T cells in the prostate TME of AA and CA patients. Lastly, the immunomodulatory potential of AZD5153, a bivalent Bromodomain 4 (BRD4) inhibitor was investigated on orthotopic prostate tumor-bearing humanized mouse models under racially defined settings, followed by comprehensive flow cytometry immunophenotypic profiling of tumor-infiltrating immune cells in the resected mice prostate tumors at clinical endpoints. Results: Prostate tumors of AA patients harbored higher proportions of CD4+ regulatory T cells (Tregs) and lower proportions of CD8+ T cells relative to CA patients. Furthermore, the immunophenotypic analysis of T cells showed higher expression of immune checkpoint molecules in AA compared to CA patients. Serum analysis revealed cytokine and chemokine expression signatures that are skewed towards a more immunosuppressive profile in AA compared to CA patients. Treatment with AZD5153 led to an increase in the survival time and a more striking reduction in tumor volume of AA-matched prostate tumor-bearing humanized mice relative to CA-matched prostate tumor-bearing humanized mice. A decrease in the proportion of tumor-infiltrating Tregs and a reduction in the expression of immune checkpoint molecules were also observed in prostate tumors from AA-matched humanized mice relative to CA-matched humanized mice. Conclusion: Our findings support the contributory role of racially distinct immunophenotypes and immune signatures in PCa disparity, and highlight the potential immunotherapeutic benefits of BRD4 inhibitors, such as AZD5153 in AA PCa patients.
Citation Format: Saheed O. Oseni, Arup Bag, Oluwaseyi Oluwatola, Natalie DeMars, Dennis Adeegbe. The immunological signatures of African American prostate cancer as biological determinants of disease disparity [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A080.