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

Author

Listed:
  • 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
    University of Pennsylvania)

  • Giorgos C. Karakousis

    (University of Pennsylvania)

  • Tara C. Mitchell

    (University of Pennsylvania
    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)

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.

Suggested Citation

  • 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 & Tatyan, 2022. "HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31713-6
    DOI: 10.1038/s41467-022-31713-6
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