Targeted epigenetic induction of mitochondrial biogenesis enhances antitumor immunity in mouse model
Targeted epigenetic induction of mitochondrial biogenesis enhances antitumor immunity in mouse model
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DOI：
10.1016/j.chembiol.2021.08.001
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发表时间：
2022-03-17
影响因子：
8.6
通讯作者：
Sugiyama，Hiroshi
中科院分区：
文献类型：
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作者：
Malinee，Madhu;Pandian，Ganesh Namasivayam;Sugiyama，Hiroshi
考虑到组合疗法在克服癌症免疫疗法现有局限性方面的潜力，越来越需要识别能够增强程序性细胞死亡蛋白 1 (PD-1) 阻断效果的免疫细胞小分子调节剂，从而实现更好的癌症治疗。尽管表观遗传药物在联合治疗中显示出潜力，但缺乏序列特异性是一个主要问题。在这里，我们鉴定并开发了一种基于 DNA 的表观遗传激活剂，具有三精氨酸载体，称为 EnPGC-1，它可以触发过氧化物酶体增殖物激活受体 - γ 共激活剂 1 α/β (PGC-1α/β) 的靶向诱导，PGC-1α/β 是线粒体生物发生的调节剂。 EnPGC-1 可增强线粒体激活、能量代谢和 CD8+T 细胞体外增殖，特别是增强氧化磷酸化，这是长寿命记忆 T 细胞的一个特征。全基因组基因分析表明，EnPGC-1 而不是对照化合物可以调节 T 细胞激活作为一个主要的生物过程。 EnPGC-1 还与 PD-1 阻断剂协同作用，增强抗肿瘤免疫力并提高宿主存活率。
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 programmed cell death protein 1 (PD-1) blockade, leading to better cancer treatment. Although epigenetic drugs showed potential in combination therapy, the lack of sequence specificity is a major concern. Here, we identify and develop a DNA-based epigenetic activator with tri-arginine vector called EnPGC-1 that can trigger the targeted induction of the peroxisome proliferator-activated receptor-gamma coactivator 1 alpha/beta (PGC-1α/β), a regulator of mitochondrial biogenesis. EnPGC-1 enhances mitochondrial activation, energy metabolism, proliferation of CD8+T cellsin vitro, and, in particular, enhances oxidative phosphorylation, a feature of long-lived memory T cells. Genome-wide gene analysis suggests 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 to enhance antitumor immunity and improved host survival.