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TIGIT Can Exert Immunosuppressive Effects on CD8+ T Cells by the CD155/TIGIT Signaling Pathway for Hepatocellular Carcinoma In Vitro.

ABSTRACT: The efficacy of adoptive cellular immunotherapy against cancer cells is limited due to the presence of immunosuppressive cells within the solid tumor microenvironment. The upregulation of certain coinhibitory receptors may lead to exhaustion of the immune effector cells. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immune inhibitory receptor expressed by regulatory T cells and activated T cells and natural killer cells. The aim of this study was to determine the immunosuppressive effects of CD155/TIGIT signaling on CD8 T cells of adoptive cellular immunotherapy in hepatocellular carcinoma (HCC). Our studies found that CD155 was overexpressed in HCC, and CD155 HCC cells upregulated TIGIT on CD8 T cells, which decreased the secretion of interferon-?, tumor necrosis factor-?, and interleukin-17A and increased that of interleukin-10 from the effector cells. However, TIGIT blockade or CD155-knockdown reversed the inhibitory effect of HCC cells on CD8 T-cell effector function. These results indicate that TIGIT can exert an immunosuppressive effect on CD8 T cells by modulating cytokine production through CD155, and is a promising target to optimize adoptive cellular immunotherapy against HCC.

SUBMITTER: Zhang C

PROVIDER: S-EPMC7566309 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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TIGIT Can Exert Immunosuppressive Effects on CD8+ T Cells by the CD155/TIGIT Signaling Pathway for Hepatocellular Carcinoma In Vitro.

Zhang Changkun C Wang Yang Y Xun Xiaodong X Wang Siqi S Xiang Xiao X Hu Shihua S Cheng Qian Q Guo Jinghang J Li Zhao Z Zhu Jiye J

Journal of immunotherapy (Hagerstown, Md. : 1997) 20201001 8

The efficacy of adoptive cellular immunotherapy against cancer cells is limited due to the presence of immunosuppressive cells within the solid tumor microenvironment. The upregulation of certain coinhibitory receptors may lead to exhaustion of the immune effector cells. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immune inhibitory receptor expressed by regulatory T cells and activated T cells and natural killer cells. The aim of this study was t ...[more]

PMID: 32804915

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Project description:It has been confirmed that the inhibitors of poly ADP-ribose polymerF(^9ase‑1 (PARP‑1) can inhibit the proliferation, apoptosis and invasion of tumor cells. However, the effects of inhibitors of PARP‑1 on hepatocellular carcinoma remain to be elucidated. The aim of the present study was to investigate the effect of three types of PARP‑1 inhibitor on the proliferation, apoptosis and migration of hepatocellular carcinoma in vitro. An MTT assay was performed to detect the proliferation of HepG2 cells following treatment with the PARP‑1 inhibitors, AG014699, BSI‑201 and AZD‑2281. Flow cytometry was used to detect the apoptosis of HepG2 cells, Western blot analysis was used to detect the protein expression of Casepase‑3, Casepase‑8, B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax), Bcl‑2, phosphatase and tensin homolog (PTEN), tissue inhibitor of metalloproteinase (TIMP) 3 and matrix metalloprotease (MMP) 3. A Transwell assay was performed to detect the migration of HepG2 cells. The results showed that AG014699, BSI‑201 and AZD‑2281 had an inhibitory effect on the proliferation of HepG2 cells in a time‑ and concentration‑dependent manner. AG014699 at concentrations of 10, 30 and 50 µmol/l, and BSI‑201 at concentrations of 20, 40 and 60 µmol/l induced the apoptosis of HepG2 cells, and the apoptotic rates were particularly high at 48 h (31, vs. 0.01%; P<0.01 and 24.12, vs. 0.03%, respectively; P<0.01). The protein expression levels of Caspase 3, Caspase 8, Bax, PTEN and TIMP 3 increased with increasing drug concentrations, whereas the protein levels of Bcl‑2 and MMP3 decreased with increasing drug concentrations, and were significantly different compared with those in the control group (P<0.01). In conclusion, AG014699, BSI‑201 and AZD‑2281 inhibitors of PARP‑1 significantly inhibited the proliferation of HepG2 cells, however, AG014699 and BSI‑201 demonstrated more sensitivity, induced apoptosis and inhibited migration of the hepatocellular carcinoma cells, which may be associated with alterations of the apoptosis signaling pathway and the expression of proteins associated with migration.

Dataset Information

TIGIT Can Exert Immunosuppressive Effects on CD8+ T Cells by the CD155/TIGIT Signaling Pathway for Hepatocellular Carcinoma In Vitro.

Publications

TIGIT Can Exert Immunosuppressive Effects on CD8+ T Cells by the CD155/TIGIT Signaling Pathway for Hepatocellular Carcinoma In Vitro.

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