2. Academic Validation
  3. USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy

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

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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