HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors

• DOI: 10.1038/s41467-022-31713-6
• Publication Date: 2022-07-14T07:02:59Z
• Authors: Lei Guan; Bin Wu; Ting Li; Lynn A. Beer; Gaurav Sharma; Mingyue Li; Chin Nien Lee; Shujing Liu; Changsong Yang; Lili Huang; Dennie T. Frederick; Genevieve M. Boland; Guangcan Shao; Tatyana M. Svitkina; Kathy Q. Cai; Fangping Chen; Meng-Qiu Dong; Gordon B. Mills; Lynn M. Schuchter; Giorgos C. Karako...; Tara C. Mitchell; Keith T. Flaherty; David W. Speicher; Youhai H. Chen; Meenhard Herlyn; Ravi K. Amaravadi; Xiaowei Xu; Wei Guo
• Keywords: 0301 basic medicine; Science; Q; Programmed Cell Death 1 Receptor; CD8-Positive T-Lymphocytes; Exosomes; Article; B7-H1 Antigen; 3. Good health; Mice; 03 medical and health sciences; Cell Line, Tumor; Tumor Microenvironment; Animals; Humans; Immunotherapy; Phosphorylation; Melanoma

AbstractThe lack of tumor infiltration by CD8+ T cells is associated with poor patient response to anti-PD-1 therapy. Understanding how tumor infiltration is regulated is key to improving treatment efficacy. Here, we report that phosphorylation of HRS, a pivotal component of the ESCRT complex involved in exosome biogenesis, restricts tumor infiltration of cytolytic CD8+ T cells. Following ERK-mediated phosphorylation, HRS interacts with and mediates the selective loading of PD-L1 to exosomes, which inhibits the migration of CD8+ T cells into tumors. In tissue samples from patients with melanoma, CD8+ T cells are excluded from the regions where tumor cells contain high levels of phosphorylated HRS. In murine tumor models, overexpression of phosphorylated HRS increases resistance to anti-PD-1 treatment, whereas inhibition of HRS phosphorylation enhances treatment efficacy. Our study reveals a mechanism by which phosphorylation of HRS in tumor cells regulates anti-tumor immunity by inducing PD-L1+ immunosuppressive exosomes, and suggests HRS phosphorylation blockade as a potential strategy to improve the efficacy of cancer immunotherapy.