PPAR-Induced Fatty Acid Oxidation in T Cells Increases the Number of Tumor-Reactive CD8+ T Cells and Facilitates Anti-PD-1 Therapy
PPAR-Induced Fatty Acid Oxidation in T Cells Increases the Number of Tumor-Reactive CD8+ T Cells and Facilitates Anti-PD-1 Therapy
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DOI：
10.1158/2326-6066.cir-18-0095
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发表时间：
2018-11-01
影响因子：
10.1
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
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作者：
Chowdhury, Partha S.;Chamoto, Kenji;Honjo, Tasuku
尽管PD-1阻断癌症免疫疗法已显示出对广泛癌症患者的潜力，但其疗效有限，部分原因是由于效应细胞毒性T淋巴细胞（CTL）通过终末分化诱导的细胞凋亡而丢失。我们先前证明，在小鼠肿瘤模型中，过氧化物酶体增殖物激活受体g（PPARg）共激活因子1-α（PGC-1 α）/转录因子复合物的激动剂对线粒体的激活与PD-1阻断单克隆抗体具有协同效应。在目前的研究中，我们研究了苯扎贝特协同作用的分子机制，苯扎贝特是PGC-1 α/PPAR复合物的激动剂，它增强了PD-1阻断的杀肿瘤作用。苯扎贝特激活CTL线粒体并上调氧化磷酸化以及糖酵解，导致幼稚T细胞的更多增殖和CTL中的效应子功能的改善。苯扎贝特还增加了脂肪酸氧化（FAO）和线粒体呼吸能力，这支持了细胞在紧急情况下的额外能量需求，使细胞存活。肉毒碱棕榈酰转移酶1（Cpt 1），这是粮农组织所需要的，和Bcl 2都上调。Cpt 1与Bcl 2可形成复合物，阻止CTL凋亡。总之，这些结果表明，苯扎贝特通过激活线粒体和细胞代谢增加或维持功能性CTL的数量，进而导致PD-1阻断期间增强的抗肿瘤免疫力。(C)2018年AACR。
Although PD-1 blockade cancer immunotherapy has shown potential for a wide range of patients with cancer, its efficacy is limited, in part, due to the loss of effector cytotoxic T lymphocytes (CTLs) via terminal differentiation-induced apoptosis. We previously demonstrated that mitochondrial activation, by the agonists of peroxisome proliferator-activated receptor g (PPARg) coactivator 1-alpha (PGC-1 alpha)/transcription factor complexes, had synergistic effects with a PD-1-blocking monoclonal antibody in a mouse tumor model. In the current study, we examined the molecular mechanismof the synergistic effects of bezafibrate, an agonist of PGC-1 alpha/PPAR complexes, which enhanced the tumoricidal effects of PD-1 blockade. Bezafibrate activated CTL mitochondria and upregulated oxidative phosphorylation as well as glycolysis, resulting in more proliferation of naive T cells and improved effector function in CTLs. Bezafibrate also increased fatty acid oxidation (FAO) and mitochondrial respiratory capacity, which supports the extra energy demands of cells in emergencies, allowing cell survival. Carnitine palmitoyl transferase 1 (Cpt1), which is needed for FAO, and Bcl2 were both upregulated. Cpt1 and Bcl2 can forma complex to prevent apoptosis of CTLs. Together, these results indicate that bezafibrate increases or maintains the number of functional CTLs by activating mitochondrial and cellular metabolism, leading in turn to enhanced antitumor immunity during PD-1 blockade. (C) 2018 AACR.