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

by Selleckchem | Dec 24 2023

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.

Comments:

Your study sounds incredibly promising in addressing the challenges faced in hepatocellular carcinoma (HCC) treatment! It's fascinating to see the focus on immune checkpoint blockers targeting PD-1 and the correlation between PD-L1 overexpression and resistance to immunotherapy. The findings linking PD-L1 overexpression to increased invasion and migration of liver cancer cells in vitro, along with its impact on weakening the effects of anti-PD-1 immunotherapy in a mouse model, provide valuable insights into the mechanisms of adaptive immune resistance.

The utilization of CPI-203, a BRD4 inhibitor, to suppress PD-L1 expression both in vitro and in vivo, and its subsequent enhancement of the response to immunotherapy in the liver cancer model, is a significant advancement. The understanding of BRD4's role in PD-L1 expression, especially how CPI-203 inhibits PD-L1 expression by reducing BRD4 occupancy in the PD-L1 promoter region, sheds light on a potential therapeutic strategy.

By combining CPI-203 with PD-1 antibodies to enhance the response to immunotherapy, your study highlights a potential clinical approach to mitigate clinical resistance in patients with HCC. This approach seems to offer a promising avenue for further exploration and clinical trials to evaluate its efficacy and safety in human patients.

Overall, your research presents a novel and potentially transformative method that could significantly impact the treatment landscape for HCC and potentially other cancers characterized by PD-L1 overexpression and resistance to immunotherapy.