USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy

  • Nat Commun. 2022 Mar 31;13(1):1700. doi: 10.1038/s41467-022-29401-6.
Wenjun Xiong   #  1  2 ,  Xueliang Gao   #  3 ,  Tiantian Zhang  2 ,  Baishan Jiang  2  4 ,  Ming-Ming Hu  2  5 ,  Xia Bu  6 ,  Yang Gao  7  8 ,  Lin-Zhou Zhang  2  9 ,  Bo-Lin Xiao  2  9 ,  Chuan He  1  2 ,  Yishuang Sun  1  2 ,  Haiou Li  2  10 ,  Jie Shi  1  2 ,  Xiangling Xiao  1  2 ,  Bolin Xiang  1  2 ,  Conghua Xie  1 ,  Gang Chen  2  9 ,  Haojian Zhang  2 ,  Wenyi Wei  8 ,  Gordon J Freeman  6 ,  Hong-Bing Shu  2  5 ,  Haizhen Wang  11 ,  Jinfang Zhang  12  13
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, 430071, Wuhan, China.
  • 2. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China.
  • 3. Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA.
  • 4. Center for Protein Degradation, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 5. Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
  • 6. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
  • 7. Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China.
  • 8. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA.
  • 9. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education and Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, 430071, Wuhan, China.
  • 10. Department of Dermatology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
  • 11. Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA. [email protected].
  • 12. Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China. [email protected].
  • 13. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, School of Medicine, Wuhan University, 430071, Wuhan, China. [email protected].
  • # Contributed equally.
PMID: 35361799 DOI: 10.1038/s41467-022-29401-6
Abstract

Anti-PD-1/PD-L1 immunotherapy has achieved impressive therapeutic outcomes in patients with multiple Cancer types. However, the underlined molecular mechanism(s) for moderate response rate (15-25%) or resistance to PD-1/PD-L1 blockade remains not completely understood. Here, we report that inhibiting the Deubiquitinase, USP8, significantly enhances the efficacy of anti-PD-1/PD-L1 immunotherapy through reshaping an inflamed tumor microenvironment (TME). Mechanistically, USP8 inhibition increases PD-L1 protein abundance through elevating the TRAF6-mediated K63-linked ubiquitination of PD-L1 to antagonize K48-linked ubiquitination and degradation of PD-L1. In addition, USP8 inhibition also triggers innate immune response and MHC-I expression largely through activating the NF-κB signaling. Based on these mechanisms, USP8 Inhibitor combination with PD-1/PD-L1 blockade significantly activates the infiltrated CD8+ T cells to suppress tumor growth and improves the survival benefit in several murine tumor models. Thus, our study reveals a potential combined therapeutic strategy to utilize a USP8 Inhibitor and PD-1/PD-L1 blockade for enhancing anti-tumor efficacy.

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