HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors
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, Guang-Can Shao, Tatyana Svitkina, Kathy Q. Cai, Fangping Chen, Meng‐Qiu Dong, Gordon B. Mills, Lynn M. Schuchter, Giorgos C. Karakousis, Tara C. Mitchell, Keith T. Flaherty, David W. Speicher, Youhai H. Chen, Meenhard Herlyn, Ravi K. Amaravadi, Xiaowei Xu, Wei Guo
Abstract
Abstract The 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.