The aggressive nature of prostate cancer of African Americans is correlated with massive down‐regulation of many immunoregulatory genes of microenvironment

Abstract

BackgroundThe overall survival of prostate cancer for African Americans (AAs) is significantly worse than for European‐Americans (EA) which cannot be attributed to social‐economic status and may be related to racial‐genetic differences. We previously applied expression analysis (U133A) and observed significantly decreased expression of AA patient compared to EA patients especially in the tumor‐adjacent stroma. We tested the hypothesis that gene express in the stroma AA patients was significantly decreased compared to EA.MethodsWe developed primary cultures of turmor‐adjacent carcinoma‐associated fibroblasts (CAFs) of AA and EA tumors and matching distant contralateral fibroblasts (dCAFs), ~100 lines in all. We examined secretion of immunomodulators from the CAFs and dCAFs from prostate cancer of AA and EA tumors and distant stroma (dCAFs) as controls and applied RNAseq of the same cells as well as archived FFPE (formal‐fixed paraffin‐embedded) blocks of AA and EA patients.ResultsAll 30 measured secreted immunomodulators were lower for AA CAFs. In contrast, few if any differences were seen between dCAFs of AA and EA. In particular Interferon‐alpha2 (IFN‐a2) is significantly reduced which is in keeping with the reduced immunomodulatory and Interferon‐induced genes (ISGs) observed for AA patients. The widespread reduction in immunomodulatory chemokines and cytokines observed in AA CAF supernatants suggests a state of significant immunosuppression as compared to the EA CAFs. The higher expression levels of chemokines Eotaxin, IP‐10, MIP1‐a, MIP‐1b, and MCP‐1, in the EA stroma may attract and activate immune cells to the tumor microenvironment thereby improving prognosis. Higher levels of several of inflammatory cytokines such as IL‐17, IL‐12, IL‐1a, IL‐1b in EA patients also may help activate immune cells leading to greater inflammation and immune responses in EA patients. The RNAseq data of AA and EA CAFs and for the FFPE tissue of AA and EA patients supported the decreased expression of the immunomodulatory genes in the stroma of AA patients compared to EA patients.ConclusionThe detection of many statistically significant differences among ISGs and other immunomodulatory genes between the races is supported by RNAseq analysis of FFPE stroma tissue and by in vitro analysis of primary tumor‐adjacent stroma indicating that differences in immunomodulatory mechanisms may be a factor in the poor prognosis of AA prostate cancer. The primary lines of AA and EA CAFs and dCAFs may be a valid system to test role of these factors.Support or Funding InformationDOD/CDMRP W81XWH‐15‐1‐0696This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.