1. Abrogation of USP7 is an alternative strategy to downregulate PD-L1 and sensitize gastric cancer cells to T cells killing
- Author
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Yi-Chao Zheng, Hong-Min Liu, Ouwen Li, Jun-Wei Wang, Zhenhe Suo, Fengyu Qi, Wen-Ting Kang, Pengxing He, Zhi-Ru Wang, and Yinghua You
- Subjects
USP18, ubiquitin specific peptidase 18 ,medicine.medical_treatment ,RIPA, radioimmunoprecipitation ,PTMs, post-translational modifications ,WB, Western blotting ,0302 clinical medicine ,General Pharmacology, Toxicology and Pharmaceutics ,HDN, well differentiated matched adjacent normal tissues ,0303 health sciences ,PDN, poor differentiated matched adjacent normal tissues ,biology ,USP7, ubiquitin-specific processing protease 7 ,HDT, well differentiated tumor tissues ,TCR, T cell receptor ,Melanoma ,DUB, deubiquitinating enzymes ,PDT, poor differentiated tumor tissues ,medicine.anatomical_structure ,PBMC, peripheral blood mononuclear cells ,030220 oncology & carcinogenesis ,GC, gastric cancer ,Original Article ,Epigenetics ,USP22, ubiquitin specific peptidase 22 ,Immunotherapy ,PD-L1 ,T cell ,TCGA, the Cancer Genome Atlas ,Cancer biology ,irAEs, immune-related adverse effects ,H2O2, hydrogen peroxidase ,TILs, tumor-infiltrating T cells ,PD-1, programmed cell death protein 1 ,03 medical and health sciences ,Immune system ,PBS, phosphate buffer saline ,Downregulation and upregulation ,CHX, cycloheximide ,medicine ,HAUSP, herpes virus-associated ubiquitin-specific protease ,EBNA1, Epstein–Barr nuclear antigen 1 ,030304 developmental biology ,Bladder cancer ,ICP0, infected cell protein 0 ,business.industry ,qRT-PCR, quantitative real time polymerase chain reaction ,lcsh:RM1-950 ,Ubiquitination ,GEPIA, Gene-Expression Profiling Interactive Analysis ,medicine.disease ,BCA, bicinchoninic acid ,MDM2, murine double minute-2 ,USP38, ubiquitin specific peptidase 38 ,FDA, U.S. Food and Drug Administration ,PD-L1, programmed death ligand-1 ,lcsh:Therapeutics. Pharmacology ,FOXO4, forkhead box O4 ,USP9X, ubiquitin specific peptidase 9 X-linked ,Cancer cell ,biology.protein ,Cancer research ,USP7 ,IL-2, interleukin 2 ,CSN5, COP9 signalosome 5 ,business ,Gastric cancer ,Immunosuppression - Abstract
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., Graphical abstract This study supports that small molecule USP7 inhibitors may be used as novel promoter of the tumor immune response.Image 1
- Published
- 2020