Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity
Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity
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DOI：
10.1073/pnas.1620433114
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发表时间：
2017-01-31
影响因子：
11.1
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
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作者：
Chamoto, Kenji;Chowdhury, Partha S.;Honjo, Tasuku
尽管通过PD-1阻断的免疫疗法显著提高了癌症患者的存活率，但需要进一步提高疗效以减少不太敏感患者的比例。在PD-1阻断治疗的小鼠模型中，我们发现引流淋巴结（DLN）中的肿瘤反应性细胞毒性T淋巴细胞（CTL）携带增加的线粒体质量和更多的活性氧（ROS）。我们表明，ROS前体或线粒体解偶联剂间接产生的ROS通过DLN和肿瘤内效应/记忆CTL的扩增协同PD-1阻断的杀肿瘤活性。这些CTL不仅携带雷帕霉素（mTOR）和AMP活化蛋白激酶（AMPK）的机制靶点的活化，而且还携带其下游转录因子如PPAR-gamma辅激活因子1 α（PGC-1a α）和T-bet的增量。此外，mTOR、AMPK或PGC-1 α的直接激活剂也协同PD-1阻断疗法，而单独的上述化学物质对肿瘤生长没有任何影响。这些发现将为开发具有PD-1阻断的新型组合疗法铺平道路。
Although immunotherapy by PD-1 blockade has dramatically improved the survival rate of cancer patients, further improvement in efficacy is required to reduce the fraction of less sensitive patients. In mouse models of PD-1 blockade therapy, we found that tumor-reactive cytotoxic T lymphocytes (CTLs) in draining lymph nodes (DLNs) carry increased mitochondrial mass and more reactive oxygen species (ROS). We show that ROS generation by ROS precursors or indirectly by mitochondrial uncouplers synergized the tumoricidal activity of PD-1 blockade by expansion of effector/ memory CTLs in DLNs and within the tumor. These CTLs carry not only the activation of mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) but also an increment of their downstream transcription factors such as PPAR-gamma coactivator 1 alpha (PGC-1a alpha) and T-bet. Furthermore, direct activators of mTOR, AMPK, or PGC-1 alpha also synergized the PD-1 blockade therapy whereas none of above-mentioned chemicals alone had any effects on tumor growth. These findings will pave a way to developing novel combinatorial therapies with PD-1 blockade.