Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing

• Published in: Acta pharmaceutica Sinica. B Vol. 11; no. 3; pp. 694 - 707
• Main Authors: Wang, Zhiru, Kang, Wenting, Li, Ouwen, Qi, Fengyu, Wang, Junwei, You, Yinghua, He, Pengxing, Suo, Zhenhe, Zheng, Yichao, Liu, Hong-Min
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2021; Elsevier
• Subjects: Cancer biology; Epigenetics; Gastric cancer; Immunosuppression; Immunotherapy; Original; PD-L1; Ubiquitination; USP7; FDA; TCR; GEPIA; USP38; CSN5; EBNA1; FOXO4; WB; H2O2; HAUSP; USP18; RIPA; DUB; Ubiquitination; CHX; Cancer biology; HDN; Immunotherapy; PD-L1; ICP0; HDT; PDN; GC; Gastric cancer; PBS; BCA; PDT; USP7; USP9X; USP22; qRT-PCR; IL-2; PBMC; TCGA; PTMs; Immunosuppression; Epigenetics; MDM2; irAEs; TILs; PD-1; PD-L1, programmed death ligand-1; IL-2, interleukin 2; USP38, ubiquitin specific peptidase 38; FOXO4, forkhead box O4; PBMC, peripheral blood mononuclear cells; CHX, cycloheximide; DUB, deubiquitinating enzymes; TILs, tumor-infiltrating T cells; GC, gastric cancer; GEPIA, Gene-Expression Profiling Interactive Analysis; WB, Western blotting; qRT-PCR, quantitative real time polymerase chain reaction; PTMs, post-translational modifications; EBNA1, Epstein–Barr nuclear antigen 1; CSN5, COP9 signalosome 5; RIPA, radioimmunoprecipitation; TCGA, the Cancer Genome Atlas; PBS, phosphate buffer saline; PDN, poor differentiated matched adjacent normal tissues; USP7, ubiquitin-specific processing protease 7; USP9X, ubiquitin specific peptidase 9 X-linked; HDN, well differentiated matched adjacent normal tissues; HAUSP, herpes virus-associated ubiquitin-specific protease; FDA, U.S. Food and Drug Administration; PDT, poor differentiated tumor tissues; BCA, bicinchoninic acid; USP18, ubiquitin specific peptidase 18; H2O2, hydrogen peroxidase; MDM2, murine double minute-2; HDT, well differentiated tumor tissues; ICP0, infected cell protein 0; USP22, ubiquitin specific peptidase 22; irAEs, immune-related adverse effects; PD-1, programmed cell death protein 1; TCR, T cell receptor
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2020.11.005

Targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for treating melanoma, gastric cancer (GC) and bladder cancer with clinical benefit. Nevertheless, many patients failed to respond to anti-PD-1/PD-L1 treatment, so it is necessary to seek an alternative strategy for traditional PD-1/PD-L1 targeting immunotherapy. Here with the data from The Cancer Genome Atlas (TCGA) and our in-house tissue library, PD-L1 expression was found to be positively correlated with the expression of ubiquitin-specific processing protease 7 (USP7) in GC. Furthermore, USP7 directly interacted with PD-L1 in order to stabilize it, while abrogation of USP7 attenuated PD-L1/PD-1 interaction and sensitized cancer cells to T cell killing in vitro and in vivo. Besides, USP7 inhibitor suppressed GC cells proliferation by stabilizing P53 in vitro and in vivo. Collectively, our findings indicate that in addition to inhibiting cancer cells proliferation, USP7 inhibitor can also downregulate PD-L1 expression to enhance anti-tumor immune response simultaneously. Hence, these data posit USP7 inhibitor as an anti-proliferation agent as well as a novel therapeutic agent in PD-L1/PD-1 blockade strategy that can promote the immune response of the tumor. This study supports that small molecule USP7 inhibitors may be used as novel promoter of the tumor immune response. [Display omitted]