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Targeted epigenetic induction of mitochondrial biogenesis enhances antitumor immunity in mouse model

Malinee, Madhu 京都大学 DOI:10.14989/doctor.k23603

2022.01.24

概要

Cancer immunotherapy by blockade of PD-1 (an immunoinhibitory receptor expressed on activated T cells) has gained exponential interest over the last decade because of long-term clinical benefits, and effectiveness over a wide-range of cancer types. However, almost half of the cancer patients show less or no response to PD-1 blockade-based monotherapy. This limitation substantiates the need of developing small-molecule based therapeutic drugs that aid to functions of effector T cells and synergize with PD-1 blockade. Recent reports suggest critical role of mitochondria in deciding T cell priming, activation and fate determination. In addition, effector T cells become less active with reduced PGC-1 expression (a known master regulator of mitochondrial metabolism and biogenesis) in the suppressive tumor microenvironment. This suggest that enhancing mitochondrial activation and biogenesis in CD8+ T cells could be an effective approach to enhance efficacy of PD-1 blockade therapy. Pyrrole–imidazole polyamides (PIPs) are small DNA ligands that can be pre-programmed to recognize target DNA sequence and guide epigenetic modulators to control the gene expression.

In this study, an epigenetic modulator termed EnPGC-1 (BI-PIP) was designed to augment the expression of PGC-1α/β. EnPGC-1 functions as a bifunctional recruiter where the BI (bromodomain inhibitor) moiety of EnPGC-1 recognizes and recruit the bromodomain (BD) of p300 and further the histone acetyl transferase (HAT) domain of p300 perform locus-specific acetylation in the PIP-binding region of PGC-1α/β. In the in vitro cell based evaluation, EnPGC-1 shown to enhance transcript and protein level of PGC-1 and PGC-1 in murine primary CD8+ T cells. EnPGC-1 enhances mitochondrial activation parameters (e.g., mass, potential, mSox) as well as mitochondrial respiration (measured by oxygen consumption rate, OCR). ChIP-sequencing analysis of H3K27Ac revealed a notable enrichment in the promoter region of both PGC-1 and PGC-1 that overlaps with EnPGC-1 binding sites. Encouraged with in vitro findings, we further tested whether EnPGC-1 synergize with PD-1 blockade therapy. EnPGC-1 in combination with PD-1 blockade accelerates the tumor clearance as well as improves the overall survival in MC38 tumorbearing hosts compared to PD-1 blockade alone or untreated group. Analysis of immune effector CD8+ T cells from draining lymph node and tumor mass post therapy shows better mitochondrial activation, mitochondrial respiration, fatty acid oxidation, and more T cell infiltration with enhanced effector functions (e.g., IFN gamma expression) to the tumor mass in the combination group. The increment in OCR/ECAR ratio supports a feature of long-live memory like population which is also evident by enhanced Bcl2 level, enhanced spare respiratory capacity and fatty acid oxidation in CD8+ T cells in combination group over PD-1 blockade alone. Moreover, genome-wide gene expression analysis in the in vitro treated CD8+ T cells suggest EnPGC-1 mediated PGC-1α/β upregulation drives differential gene expression that regulates T cell activation, proliferation, OXPHOS and FAO in CD8+ T cells compared to control groups.

The data generated by independent lines of evidence, suggested the recruitment of p300 acetyltransferase as the potential mechanism of EnPGC-1-mediated gene activation. This study underscores the novel clinical application of first DNA-based designer molecule, EnPGC-1, for therapeutic purposes in the cancer treatment of less responsive cancer patients by combination therapy of EnPGC-1 with PD-1 blockade.

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Please cite this article in press as: Malinee et al., Targeted epigenetic induction of mitochondrial biogenesis enhances antitumor immunity in mouse model, Cell Chemical Biology (2021), https://doi.org/10.1016/j.chembiol.2021.08.001

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