Ethnic differences in the immune landscape and gene signature in prostate cancer

Prostate cancer is a biologically and clinically heterogeneous disease, with incidence and mortality rates that vary substantially across racial and ethnic groups. Among Black American (BA) men, the incidence of prostate cancer is approximately 60% higher, and the mortality rate is two to three times greater than that observed in White American (WA) men. These disparities are multifactorial, involving both biological and social determinants such as genetic predisposition, comorbidities, socioeconomic status, environmental exposures, and cultural influences. While these factors obviously contribute to disease outcomes, growing evidence highlights the crucial role of the tumor immune microenvironment and its associated gene signatures in shaping prostate cancer biology and progression. To investigate ethnic variations in tumor immune gene signatures, we analyzed transcriptomic data from 35 radical prostatectomy specimens from treatment-naïve patients, including 20 BA and 15 WA men. Gene expression profiles from tumor and adjacent normal tissues were examined using EPIC, xCell, and Ingenuity Pathway Analysis. Differential gene expression was determined by rank testing, and prognostic associations were assessed via univariate Cox regression. WA tumors are enriched for pathways associated with neuroinflammation and oxidative phosphorylation including IL-8 signaling, neuroinflammation, dendritic cell maturation, oxidative phosphorylation, PKCθ signaling in T cells, and NFAT-mediated immune regulation, while PPAR and PD-1/PD-L1 pathways were less active. In contrast, BA tumors are characterized by increased activation of pro-inflammatory and immune-regulatory pathways; display elevated CREB signaling, Th1/Th2 activation, dendritic cell maturation, IL-17 and TREM1 signaling, and IL-17A/F-mediated cytokine production, with reduced activity in PD-1/PD-L1, ILK, IL-3, VEGF, and B-cell receptor pathways. Thirteen immune cell types showed race-specific gene expression patterns including ARG1, FA2H, FBXO39, IGLL3P, KLKB1, MERTK, SEMA3G, and TRPV5 markedly expressed in WA tumors, whereas ARSL, BAALC, CCL23, EPHA2, IGFL2, KRT5, NTM, and NDP upregulated in BA tumors. These results reveal distinct immune-oncological landscapes between BA and WA prostate tumors, highlighting pro-inflammatory pathway enrichment in BA men and underscoring opportunities for ethnicity-specific, genomically informed therapies.