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

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.

• 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 Karakousis, Tara C Mitchell, Keith T Flaherty, David W Speicher, Youhai H Chen, Meenhard Herlyn, Ravi K Amaravadi, Xiaowei Xu, Wei Guo
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 4078 (07 14 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35835783 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022. The Author(s).

Chemical References

• B7-H1 Antigen
• Programmed Cell Death 1 Receptor

Topics

• Animals
• B7-H1 Antigen
• CD8-Positive T-Lymphocytes
• Cell Line, Tumor
• Exosomes (metabolism)
• Humans
• Immunotherapy
• Melanoma
• Mice
• Phosphorylation
• Programmed Cell Death 1 Receptor
• Tumor Microenvironment