Targeted Epigenetic Induction of Mitochondrial Biogenesis Enhances Antitumor Immunity in Mouse Model

Abstract

Here, we prepared a library of pyrrole–imidazole polyamides, PIPs encompassing the P300/CBP-selective bromodomain inhibitor (BI), which acts as a P300/CBP recruiter, and identified a PIP called BI-PIP-R that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1 α/β), a regulator of mitochondrial activation and biogenesis. We further improved the chemical architecture of this PIP using a tri-arginine vector to generate a designer dual-functional molecule termed EnPGC-1 that enhanced mitochondrial activation, energy metabolism, proliferation of CD8+ T cells in vitro, and, in particular, enhanced oxidative phosphorylation (OXPHOS), a feature of long-lived memory T cells.  Collectively, the ability of EnPGC-1 to synergize with PD-1 checkpoint blockade represents the first example of a programmable DNA-based epigenetic drug with the potential to overcome the existing issues in cancer immunotherapy.

Keywords: mitochondrial activation, antitumor immunity, PD-1 blockade, Pyrrole-imidazole polyamide, P300/CBP