Single-cell profiling of peripheral blood mononuclear cells in diverse men with prostate cancer reveals a fatal disease-associated immune signature.

Alterations in peripheral immunity may contribute to fatal prostate cancer and the excessive disease burden among African American (AA) men. Thus, we investigated peripheral immunity in prostate cancer patients in association with disease outcome and AA descent. We performed single-cell RNA and T cell receptor (TCR) sequencing using peripheral blood mononuclear cells (PBMC) from a cohort of 43 prostate cancer patients with survival follow-up and 16 healthy controls. Analyzing 273,229 high-quality PBMC, we observed that men who developed fatal prostate cancer (n=20) distinctively expressed the LAG3 and TIGIT exhaustion markers in their CD8⁺ T effector memory cells (CD8 TEM). These men also showed a loss of type-2 conventional dendritic cells (cDC2). Further analyses revealed additional transcriptome-inferred functional differences in cDC2, CD16+ monocytes, and CD8 TEM comparing men with and without fatal disease. Those describe cDC2 as immunosuppressed, CD16+ monocytes as pro-inflammatory but less cytotoxic, and CD8 TEM as chronically activated in patients with fatal disease. Comparing AA with European American patients, we observed upregulated LAG3 and TIGIT in AA PBMC. For cDC2 and CD16+ monocytes, fatal disease and AA patients showed shared marker expression. Furthermore, TCR profiling discovered over-representation of large, hyperexpanded clonotypes and a lower TCR diversity among fatal disease and AA patients. Lastly, the CD8 TEM functional status and LAG3 expression in PBMC emerged as a candidate predictor of disease fatality. We conclude that peripheral immunity may distinctly vary in association with disease outcome and AA descent of prostate cancer patients.