CPI‐203 improves the efficacy of anti‐PD‐1 therapy by inhibiting the induced PD‐L1 overexpression in liver cancer. Issue 1 (18th November 2021)

• Record Type: Journal Article
• Authors: Niu, Xiaoge; Wang, Wei; Liang, Taizhen; Li, Shasha; Yang, Chan; Xu, Xinfeng; Li, Lin; Liu, Shuwen
• Is Part Of: Cancer science. Volume 113:Issue 1(2022)
• Page Start: 28
• Page End: 40
• Publication Date: 2021-11-18
• Subjects: BRD4 inhibitor -- IFN‐γ -- immunotherapy -- liver cancer -- PD‐L1; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.15190
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: 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 PD‐L1 expression in vitro and in vivo, combined with PD‐1 antibody improved the response to immunotherapy in a liver cancer model. Cell transfection and chromatin immunoprecipitation assay manifested that BRD4 plays a key role in PD‐L1 expression; CPI‐203 can inhibit PD‐L1 expression 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 patients with HCC. Abstract : Antibodies that block the PD‐1/PD‐L1 inhibition axis activate tumor‐specific T cells producing IFN‐γ, but continuous IFN‐γ leads to a PD‐L1 expression increase in tumor cells, which can engage the PD‐1 receptor on T cells to suppress antitumor immunity. CPI‐203, which can inhibit immunotherapy‐induced PD‐L1 expression, provides the conditions for efficacy of anti‐PD‐1 immunotherapy.