Single cell profiling of peripheral blood mononuclear cells in diverse men with prostate cancer reveals lethal disease-associated immune signatures

Purpose: Prostate cancer disproportionately affects men of African ancestry (AA), who also exhibit a distinct immunobiological profile. We aimed to investigate the composition and gene expression patterns of circulating peripheral blood mononuclear cells (PBMCs) in AA and European American (EA) prostate cancer patients, and to evaluate their association with ancestry and lethal prostate cancer outcomes. Experimental Design: We performed single-cell RNA sequencing (scRNA-seq) on 273,229 high-quality PBMCs isolated from 59 prostate cancer patients and healthy controls, along with single-cell TCR and BCR sequencing (scTCR-seq and scBCR-seq) in 53 individuals of African American (AA) and European American (EA) ancestry. Immune cell subpopulations were characterized, and differential gene expression and pathway analyses were conducted to identify ancestry-related differences and signatures associated with lethal disease. Results: Prostate cancer patients showed increased CD4⁺ cytotoxic and CD8⁺ effector memory T cells, with reduced CD4⁺ naïve and CD56 bright NK cells, indicating immune activation and dysregulation. AA patients had elevated CD4⁺ CTLs and cDC1s and fewer CD56 bright NK cells compared to EA. Lethal cases showed reduced cDC2s, suggestive of impaired immune priming. CD16⁺ monocytes shared 98 genes and 9 pathways across race and lethality contrasts, including enhanced interferon signaling in AA patients. Inflammatory and cytokine pathways—especially TNFα and NF-κB—were enriched in AA and in lethal disease, indicating shared immune dysregulation. TCR profiling revealed more large and hyperexpanded clonotypes in lethal cases, reflecting antigen-driven T cell responses and potential exhaustion. BCR sequencing showed reduced repertoire diversity and greater clonal dominance in lethal and EA patients, consistent with skewed humoral responses. Conclusions: Our findings reveal ancestry- and lethality-associated immune differences in prostate cancer. Elevated T cell exhaustion and inflammatory signaling in AA patients correlated with poor outcomes, highlighting potential ancestry-informed biomarkers and targets. Expanded T and B cell clones in lethal cases suggest antigen-driven immune activation with possible dysfunction.