CPI-203 improves the efficacy of anti-PD-1 therapy by inhibiting the induced PD-L1 overexpression in liver cancer.

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.

• Authors: Xiaoge Niu, Wei Wang, Taizhen Liang, Shasha Li, Chan Yang, Xinfeng Xu, Lin Li, Shuwen Liu
• Journal: Cancer science (Cancer Sci) Vol. 113 Issue 1 Pg. 28-40 (Jan 2022) ISSN: 1349-7006 [Electronic] England
• PMID: 34727389 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Acetamides
• Azepines
• B7-H1 Antigen
• BRD4 protein, human
• CD274 protein, human
• CPI203
• Cell Cycle Proteins
• Immune Checkpoint Inhibitors
• Transcription Factors

Topics

• Acetamides (administration & dosage, pharmacology)
• Animals
• Azepines (administration & dosage, pharmacology)
• B7-H1 Antigen (genetics)
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Drug Synergism
• Gene Expression Regulation, Neoplastic (drug effects)
• Hep G2 Cells
• Humans
• Immune Checkpoint Inhibitors (administration & dosage, pharmacology)
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Male
• Mice
• Promoter Regions, Genetic (drug effects)
• Transcription Factors (metabolism)
• Tumor Escape (drug effects)
• Tumor Microenvironment (drug effects)
• Up-Regulation (drug effects)
• Xenograft Model Antitumor Assays