A PD1 targeted nano-delivery system based on epigenetic alterations of T cell responses in the treatment of gastric cancer

Abstract

The anticancer effects of immune checkpoint inhibitors (ICIs) have been widely examined recently. Although ICIs have been progressively improved for successful gastric cancer treatment, different trials of ICIs such as pembrolizumab and nivolumab have yielded widely variable response rates. Strategies to further improve the efficacy of ICIs are still needed. Previous studies have shown that de novo DNA methylation is acquired by PD1+CD8+ tumor-infiltrating T cells (TILs), which cause a hierarchical downregulation of cytokines such as interferon-γ (IFN-γ). The epigenetic agent 5-Aza-2′-deoxycytidine (DAC) blocks de novo DNA methylation in activated PD1+CD8+ TILs. Such a feature might help enhance the anti-tumor effect of immune checkpoint blockade (ICB) treatment. In this study, polyethylene glycol-poly(ε-caprolactone) (PEG-PCL) nanoparticles (NPs) were linked to the anti-programmed death-1 monoclonal antibody nivolumab to yield αPD1-NPs for targeting TILs with PD1 overexpression using DAC. In addition, the NPs increased DAC stability and improved IFN-γ secretion and the anti-tumor effect of ICB in vitro. Therefore, targeted delivery of DAC reverses the exhaustion of PD1+CD8+ TILs and improves T cell responses and the treatment effect of ICB. These findings suggest that nivolumab-NPs are a potential tool for the delivery of epigenetic drugs, which could enhance the anti-tumor effect of ICB in gastric cancer.

Keywords

• PD1
• nano-delivery system
• epigenetic alteration
• T cell immune response
• gastric cancer