Cancer Sci. 2021 Nov 2. doi: 10.1111/cas.15190. Online ahead of print.
Hepatocellular carcinoma (HCC) is one of the commonest lethal malignancies worldwide, and often diagnosed at an advanced stage, without any curative therapy. Immune checkpoint blockers targeting the programmed death receptor 1 (PD-1) have shown impressive antitumor activity in patients with advanced-stage HCC, while the response rate is only 30%. Inducible PD-L1 overexpression may result in a lack of response to cancer immunotherapy, which is attributed to a mechanism of adaptive immune resistance. Our study investigated that the overexpression of PD-L1 promoted the invasion and migration of liver cancer cells in vitro, and the induced overexpression of PD-L1 in the tumor microenvironment could weaken the effects of anti-PD-1 immunotherapy in a BALB/c mouse model of liver cancer. CPI-203, a small-molecule bromodomain-containing protein 4 (BRD4) inhibitor, which can potently inhibit the PD-L1 expression in vitro and vivo, combined with PD-1 antibody improved the response to immunotherapy in a liver cancer model. Cell-transfection and the chromatin immunoprecipitation assay manifested that BRD4 plays a key role in PD-L1 expression, CPI-203 can inhibit the expression of PD-L1 by inhibiting the BRD4 occupation of the PD-L1 promoter region. This study indicates a potential clinical immunotherapy method to reduce the incidence of clinical resistance to immunotherapy in HCC patients.
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