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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Cancer

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