Single-cell analysis of localized prostate cancer patients links high Gleason score with an immunosuppressive profile

Evading immune surveillance is a hallmark for the development of multiple cancer types. Whether immune evasion contributes to the pathogenesis of high-grade prostate cancer (HGPCa) remains an area of active inquiry.

Through single-cell RNA sequencing and multicolor flow cytometry of freshly isolated prostatectomy specimens and matched peripheral blood, we aimed to characterize the tumor immune microenvironment (TME) of localized prostate cancer (PCa), including HGPCa and low-grade prostate cancer (LGPCa).

HGPCa are highly infiltrated by exhausted CD8⁺ T cells, myeloid cells, and regulatory T cells (TRegs). These HGPCa-infiltrating CD8⁺ T cells expressed high levels of exhaustion markers including TIM3, TOX, TCF7, PD-1, CTLA4, TIGIT, and CXCL13. By contrast, a high ratio of activated CD8⁺  effector T cells relative to TRegs and myeloid cells infiltrate the TME of LGPCa. HGPCa CD8⁺  tumor-infiltrating lymphocytes (TILs) expressed more androgen receptor and prostate-specific membran antigen yet less prostate-specific antigen than the LGPCa CD8⁺  TILs. The PCa TME was infiltrated by macrophages but these did not clearly cluster by M1 and M2 markers.

Our study reveals a suppressive TME with high levels of CD8⁺ T cell exhaustion in localized PCa, a finding enriched in HGPCa relative to LGPCa. These studies suggest a possible link between the clinical-pathologic risk of PCa and the associated TME. Our results have implications for our understanding of the immunologic mechanisms of PCa pathogenesis and the implementation of immunotherapy for localized PCa.