USP22 Deubiquitinates CD274 to Suppress Anticancer Immunity

  • Cancer Immunol Res. 2019 Oct;7(10):1580-1590. doi: 10.1158/2326-6066.CIR-18-0910.
Xing Huang  #  1  2 ,  Qi Zhang  3  4  5 ,  Yu Lou  3  4  5 ,  Junli Wang  3  4  5 ,  Xinyu Zhao  3  4  5 ,  Lin Wang  3 ,  Xiaozhen Zhang  #  3  4  5 ,  Shanshan Li  3 ,  Yulan Zhao  3 ,  Qi Chen  3  4  5 ,  Tingbo Liang  1  4  5 ,  Xueli Bai  1  4  5
Affiliations
  • 1. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. [email protected] [email protected] [email protected].
  • 2. The Key Laboratory of Developmental Genes and Human Disease, Institute of Life Sciences, Southeast University, Nanjing, Jiangsu, China.
  • 3. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 4. Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
  • 5. Innovation Center for the Study of Pancreatic Diseases, Zhejiang Province, Hangzhou, Zhejiang, China.
  • # Contributed equally.
PMID: 31399419 DOI: 10.1158/2326-6066.CIR-18-0910
Abstract

PD-1 (CD279)-PD-L1 (CD274) inhibitory signaling is critical for Cancer immune evasion, and thus has become one of the major targets in Anticancer immunotherapy. There are several studies that demonstrate the potent effects of posttranslational modifications of CD274 on immune inactivation and suppression, such as ubiquitination, phosphorylation, glycosylation, and palmitoylation. However, the regulatory mechanisms for CD274 deubiquitination are still largely unclear. Here, we identified Ubiquitin-Specific Protease 22 (USP22) as a novel Deubiquitinase of CD274. USP22 directly interacted with the C terminus of CD274, inducing its deubiquitination and stabilization. Across multiple Cancer types, USP22 was highly expressed and frequently altered in liver Cancer, closely correlating with poor prognosis of these patients. Genetic depletion of USP22 inhibited liver Cancer growth in an immune system-dependent manner, increased tumor immunogenicity and tumor-infiltrating lymphocytes, and improved therapeutic efficacy of CD274-targeted immunotherapy and CDDP-based chemotherapy in mice. We demonstrate that targeting USP22 is a promising strategy to potentiate Anticancer immunity for CD274-amplified Cancer.