ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy

  • Nat Commun. 2023 May 19;14(1):2859. doi: 10.1038/s41467-023-38605-3.
Xiangling Xiao  #  1  2 ,  Jie Shi  #  1  2 ,  Chuan He  #  1  2 ,  Xia Bu  3 ,  Yishuang Sun  1  2 ,  Minling Gao  1  2 ,  Bolin Xiang  1  2 ,  Wenjun Xiong  1  2 ,  Panpan Dai  1 ,  Qi Mao  1  2 ,  Xixin Xing  1  2 ,  Yingmeng Yao  1  2 ,  Haisheng Yu  1  2 ,  Gaoshan Xu  1  2 ,  Siqi Li  4 ,  Yan Ren  5 ,  Baoxiang Chen  6 ,  Congqing Jiang  6 ,  Geng Meng  7 ,  Yu-Ru Lee  8 ,  Wenyi Wei  9 ,  Gordon J Freeman  3 ,  Conghua Xie  10 ,  Jinfang Zhang  11  12
Affiliations
  • 1. Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University; Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
  • 2. Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China.
  • 3. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 4. Department of Biology, University of Copenhagen, Copenhagen, 2100, Denmark.
  • 5. Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 6. Department of Colorectal and Anal Surgery, Low Rectal Cancer Diagnosis and Treatment Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 7. College of Veterinary Medicine, China Agricultural University, Beijing, 100094, China.
  • 8. Institute of Biomedical Sciences, Academia Sinica, Taipei, 115201, Taiwan.
  • 9. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.
  • 10. Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University; Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, 430071, China. [email protected].
  • 11. Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University; Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, 430071, China. [email protected].
  • 12. Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, 430071, China. [email protected].
  • # Contributed equally.
PMID: 37208329 DOI: 10.1038/s41467-023-38605-3
Abstract

The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting Cancer immune evasion. While ubiquitin E3 Ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the Ubiquitin-Specific Protease 5 (USP5) as a bona fide Deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.

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