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, 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 and Wei Guo ()
Additional contact information
Lei Guan: University of Pennsylvania
Bin Wu: University of Pennsylvania
Ting Li: University of Pennsylvania
Lynn A. Beer: Wistar Institute
Gaurav Sharma: University of Pennsylvania
Mingyue Li: University of Pennsylvania
Chin Nien Lee: University of Pennsylvania
Shujing Liu: University of Pennsylvania
Changsong Yang: University of Pennsylvania
Lili Huang: University of Pennsylvania
Dennie T. Frederick: Harvard Medical School
Genevieve M. Boland: Massachusetts General Hospital
Guangcan Shao: National Institute of Biological Sciences
Tatyana M. Svitkina: University of Pennsylvania
Kathy Q. Cai: Fox Chase Cancer Center
Fangping Chen: The Wistar Institute
Meng-Qiu Dong: National Institute of Biological Sciences
Gordon B. Mills: Oregon Health & Science University
Lynn M. Schuchter: University of Pennsylvania
Giorgos C. Karakousis: University of Pennsylvania
Tara C. Mitchell: University of Pennsylvania
Keith T. Flaherty: Harvard Medical School
David W. Speicher: Wistar Institute
Youhai H. Chen: University of Pennsylvania
Meenhard Herlyn: Wistar Institute
Ravi K. Amaravadi: University of Pennsylvania
Xiaowei Xu: University of Pennsylvania
Wei Guo: University of Pennsylvania

Nature Communications, 2022, vol. 13, issue 1, 1-12

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.

Date: 2022
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DOI: 10.1038/s41467-022-31713-6

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