Boosting PD-1 blockade cancer immunotherapy by modulating T cell metabolism

最近，利用抗体阻断免疫系统的关键负调节因子（PD-1），由于其对多种癌症的持久作用，导致了癌症药物发现领域的范式转变，被称为PD-1阻断癌症免疫疗法。然而，相当数量的患者对这种治疗没有反应。因此，必须开发提高PD-1阻断疗效的联合疗法。为了克服PD-1阻断治疗的低反应率，各种组合已被使用。但是，许多临床试验报告并没有显示出令人鼓舞的结果。我们最近证明，贝扎布特激活PGC-1α（线粒体生物发生的关键调节因子）/过氧化物酶体增殖物激活受体（PPARs）可提高PD-1阻断的疗效。然而，通过激活PPAR通路而产生抗肿瘤免疫的机制尚不清楚。在这项研究中，我们研究了贝扎贝特对效应T细胞表型及其线粒体活性的影响，并研究了贝扎贝特调节ctl分化和增强T细胞抗肿瘤免疫的分子机制。我们发现贝扎菲特上调脂肪酸氧化，抑制效应T细胞凋亡。贝扎布特对效应期的影响导致效应T细胞数量增加，并通过PD-1阻断增强肿瘤杀伤作用。因此，在T细胞中激活PPAR信号可能是一种有希望的PD-1阻断联合治疗策略。

Recently blockade of a key negative regulator (PD-1) of immune system using antibody has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers and is termed as PD-1 blockade cancer immunotherapy. However, a substantial number of patients do not respond to this therapy. Thus, combination therapy to improve PD-1 blockade efficacy must be developed. To overcome the low response rate of PD-1 blockade therapy, various combinations have been used. But, many clinical trial reports have not shown encouraging results. We recently demonstrated that activation of PGC-1α, a key regulator of mitochondrial biogenesis, /peroxisome proliferator-activated receptors (PPARs) by bezafibrate improves the efficacy of PD-1 blockade. However, the mechanism of anti-tumor immunity development by activation of the PPAR pathway remains unknown. In this study, we investigated the effect of bezafibrate on phenotype of effector T cells and its mitochondrial activities followed by investigation of the molecular mechanism of how bezafibrate modulates the differentiation of CTLs and enhances T cell-based anti-tumor immunity. We found that bezafibrate upregulates fatty acid oxidation and inhibits the apoptosis of effector T cells. This effect of bezafibrate on the effector phase resulted in an increased number of effector T cells and augmentation of tumoricidal effect by PD-1 blockade. Therefore, PPAR signal activation in T cells may be a promising strategy for PD-1 blockade combination therapy.