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
  • 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. [email protected].
  • # 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.

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