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

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

PROVIDER: PRJNA731459 | ENA |

REPOSITORIES: ENA

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Project description:Cancer immunotherapy using monoclonal antibodies (mAbs) to immune checkpoint (e.g., PD-1) has revolutionized the cancer treatments with long-term clinical benefits and being applicable to a wide range of tumors. However, a significant fraction of cancer patients does not respond to PD-1 blockade-based monotherapy. Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of PD-1 blockade, leading to better cancer treatment. Although epigenetic drugs have shown potential in combination therapy, the lack of sequence specificity is a major concern. Pyrrole–imidazole polyamide (PIP), a selective DNA-binding small molecule, can guide epigenetic modulators to enable targeted gene activation. Here, we prepared and screened a library of PIPs encompassing the distinct PIPs conjugated with 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-1a/b), a regulator of mitochondrial activation and biogenesis. We further improved the chemical architecture of BI-PIP-R using a tri-arginine vector for better nuclear accumulation. This 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. Genome-wide gene analysis also suggested that EnPGC-1 and not the control compounds can regulate T cell activation as a major biological process. EnPGC-1 also synergizes with PD-1 blockade that enhances antitumor immunity and improves the survival. Together, this study represents the first example of a programmable DNA-based epigenetic drug with the potential to overcome the existing issues in cancer immunotherapy.

Project description:Cancer immunotherapy using monoclonal antibodies (mAbs) to immune checkpoint (e.g., PD-1) has revolutionized the cancer treatments with long-term clinical benefits and being applicable to a wide range of tumors. However, a significant fraction of cancer patients does not respond to PD-1 blockade-based monotherapy. Considering the potential of combinatorial therapies in overcoming existing limitations of cancer immunotherapy, there is an increasing need to identify small-molecule modulators of immune cells capable of augmenting the effect of PD-1 blockade, leading to better cancer treatment. Although epigenetic drugs have shown potential in combination therapy, the lack of sequence specificity is a major concern. Pyrrole–imidazole polyamide (PIP), a selective DNA-binding small molecule, can guide epigenetic modulators to enable targeted gene activation. Here, we prepared and screened a library of PIPs encompassing the distinct PIPs conjugated with 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-1a/b), a regulator of mitochondrial activation and biogenesis. We further improved the chemical architecture of BI-PIP-R using a tri-arginine vector for better nuclear accumulation. This 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. Genome-wide gene analysis also suggested that EnPGC-1 and not the control compounds can regulate of T cell activation as a major biological process. EnPGC-1 also synergized with PD-1 blockade to enhance antitumor immunity and improved the survival. Together, this study represents the first example of a programmable DNA-based epigenetic drug with the potential to overcome the existing issues in cancer immunotherapy.

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

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