Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy
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DOI：
10.7554/elife.52330
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发表时间：
2020-03-03
期刊：
影响因子：
7.7
通讯作者：
Honjo, Tasuku
中科院分区：
文献类型：
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作者：
Kumar, Alok;Chamoto, Kenji;Honjo, Tasuku
PD-1阻断疗法彻底改变了癌症治疗。然而，大量患者无反应。为了挽救无反应的患者，必须阐明PD-1阻断治疗无反应的机制。使用“双侧肿瘤模型”，其中反应性和无反应性肿瘤接种到小鼠腹部的不同侧，我们证明了无反应性肿瘤可以分为两组：有和没有全身免疫抑制特性（SIP）。SIP阳性肿瘤释放出非特征性的非蛋白质小分子，抑制线粒体活化和T细胞增殖。相比之下，SIP阴性B16肿瘤通过失去MHC I类表达而逃避免疫。SIP阳性肿瘤的无反应性通过用线粒体激活剂改善线粒体功能而部分克服;这对于B16是不成功的，其采用免疫忽略。这些结果表明，“双侧肿瘤模型”是有用的分层肿瘤研究无反应性的机制，并制定一个战略，适当的联合治疗。
PD-1 blockade therapy has revolutionized cancer treatments. However, a substantial population of patients is unresponsive. To rescue unresponsive patients, the mechanism of unresponsiveness to PD-1 blockade therapy must be elucidated. Using a 'bilateral tumor model' where responsive and unresponsive tumors were inoculated into different sides of the mouse belly, we demonstrated that unresponsive tumors can be categorized into two groups: with and without systemic immunosuppressive property (SIP). The SIP-positive tumors released uncharacterized, nonproteinaceous small molecules that inhibited mitochondrial activation and T cell proliferation. By contrast, the SIP-negative B16 tumor escaped from immunity by losing MHC class I expression. Unresponsiveness of SIP-positive tumors was partially overcome by improving the mitochondrial function with a mitochondrial activator; this was not successful for B16, which employs immune ignorance. These results demonstrated that the 'bilateral tumor model' was useful for stratifying tumors to investigate the mechanism of unresponsiveness and develop a strategy for proper combination therapy.