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

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

  • Nat Commun. 2022 Jul 14;13(1):4078. doi: 10.1038/s41467-022-31713-6.
Lei Guan  # 1,  Bin Wu  # 1,  Ting Li  # 2,  Lynn A Beer 3,  Gaurav Sharma 4,  Mingyue Li 2,  Chin Nien Lee 2,  Shujing Liu 2,  Changsong Yang 1,  Lili Huang 2,  Dennie T Frederick 5,  Genevieve M Boland 6,  Guangcan Shao 7,  Tatyana M Svitkina 1,  Kathy Q Cai 8,  Fangping Chen 9,  Meng-Qiu Dong 7,  Gordon B Mills 10,  Lynn M Schuchter 4 11,  Giorgos C Karakousis 2,  Tara C Mitchell 4 11,  Keith T Flaherty 5,  David W Speicher 3,  Youhai H Chen 2,  Meenhard Herlyn 3,  Ravi K Amaravadi 4,  Xiaowei Xu 2,  Wei Guo 12
Affiliations

Affiliations

  • 1 Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 2 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 3 Molecular & Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA, 19104, USA.
  • 4 Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 5 Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA.
  • 6 Department of Surgical Oncology, Massachusetts General Hospital, Boston, MA, MA02114, USA.
  • 7 National Institute of Biological Sciences, Beijing, 102206, P. R. China.
  • 8 Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.
  • 9 Histotechnology Facility, The Wistar Institute, Philadelphia, PA, 19104, USA.
  • 10 Division of Oncological Science, School of Medicine and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97201, USA.
  • 11 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
  • 12 Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, PA, 19104, USA. guowei@sas.upenn.edu.
  • # Contributed equally.
PMID: 35835783 DOI: 10.1038/s41467-022-31713-6
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15816
    99.95%, ERK1/3抑制剂
    ERK
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