Prostate Cancer Cells Secrete PD-1 in Exosomes to Enhance Myeloid-Derived Suppressor Cell Activity and Promote Tumor Immune Evasion.

UNLABELLED: PD-1 restrains effective killing of cancer cells by the immune system and is predominantly located on the surface of T cells or other immune cells. However, cancer cells also express PD-1 to varying degrees, which is commonly associated with a poor prognosis. In this study, we investigated the regulation and function of PD-1 expression in prostate cancer and revealed the impact on the tumor microenvironment. PD-1 expression in cancer cells positively correlated with Gleason grade and metastasis but negatively correlated with CD8+ T-cell infiltration in patients with prostate cancer. Prostate cancer cells secreted PD-1 in exosomes that enhanced the activity of myeloid-derived suppressor cells by activating JAK/STAT3 signaling. The activated myeloid-derived suppressor cells in turn reduced the infiltration of CD8+ T cells within the tumor, promoting tumor immune evasion. The ubiquitin-specific peptidase 7 (USP7) induced deubiquitination and elevated the abundance of PD-1 in prostate cancer, and USP7 inhibition sensitized prostate cancer tumors to anti-PD-1 antibody treatment. Given the modest efficacy of current immunotherapeutic approaches for prostate cancer, strategies to inhibit the secretion of PD-1-bearing exosomes or USP7 function may emerge as promising immunostimulatory interventions for treating prostate cancer.

SIGNIFICANCE: PD-1 is elevated in prostate cancer by USP7 and secreted in exosomes to activate myeloid-derived suppressor cells and shape an immune-suppressive microenvironment, providing therapeutic targets to improve immunotherapy efficacy.