Prostate Cancer Cells Secrete PD-1 in Exosomes to Enhance Myeloid-Derived Suppressor Cell Activity and Promote Tumor Immune Evasion
Jie Zhang, Weiwu Chen, Chen Zhang, Qian He, Xudong Wang, Jiayu Han, Peng Gao, Kunyu Wang, Hanhui Xie, Feng Gao, Yining Guo, Wenhao Guo, Haofei Jiang, Jing Le, Ruichen Zang, Sisi Mo, Haobo Fan, Xiaoxiao Zhu, Xinrong Jiang, Fengbin Gao, Yanlan Yu, Guoqing Ding, Yicheng Chen
Abstract
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.