Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer

Area of Science:

• Oncology
• Epigenetics
• Immunotherapy

Background:

• Epigenetic alterations in tumor and immune cells are key in bladder cancer (BC) development.
• Histone deacetylase (HDAC) inhibitors offer a promising therapeutic avenue for BC.

Purpose of the Study:

• To investigate the effects of a novel HDAC inhibitor, CM-1758, on bladder cancer (BC) cells and its potential combination with immune checkpoint inhibitors (ICI).
• To explore the epigenetic regulation of PD-L1 by CM-1758 and its impact on the tumor microenvironment.

Main Methods:

• In vitro studies on various BC cell lines to assess CM-1758's cytotoxic and cytostatic effects.
• In vivo studies using a syngeneic mouse model of metastatic BC to evaluate CM-1758 alone and in combination with anti-PD-L1.
• Analysis of transcriptional changes, PD-L1 epigenetic regulation, tumor growth, immune cell infiltration, and macrophage polarization.

Main Results:

• CM-1758 demonstrated cytotoxic and cytostatic effects on BC cells by inducing apoptosis and cell cycle arrest at low micromolar concentrations.
• CM-1758 treatment upregulated PD-L1 expression, which is epigenetically regulated by histone acetylation.
• In vivo, CM-1758 significantly delayed tumor growth and increased CD8+ T cell infiltration.
• Combination therapy reprogramed macrophages to an M1-like state and increased systemic pro-inflammatory cytokines.

Conclusions:

• CM-1758 exhibits significant antitumor activity in bladder cancer models.
• Combining HDAC inhibitors like CM-1758 with immunotherapies, such as anti-PD-L1, holds potential for managing advanced metastatic BC by modulating the tumor microenvironment and enhancing anti-tumor immunity.