CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation
CD28 costimulation drives tumor-infiltrating T cell glycolysis to promote inflammation
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DOI：
10.1172/jci.insight.138729
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发表时间：
2020-08-20
期刊：
影响因子：
8
通讯作者：
Rathmell, Jeffrey C.
中科院分区：
文献类型：
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作者：
Beckermann, Kathryn E.;Hongo, Rachel;Rathmell, Jeffrey C.
代谢重编程决定了受刺激的T细胞的命运和功能，但这些途径可以在肿瘤微环境中的T细胞中被抑制。我们先前表明，糖酵解和线粒体适应直接有助于降低肾细胞癌（RCC）CD 8（+）肿瘤浸润淋巴细胞（TIL）的效应功能。在这里，我们定义了这些代谢途径在CD 8 + RCC TIL的激活和效应功能中的作用。CD 28共刺激在增强T细胞活化和代谢中起关键作用，并且被抑制性和检查点免疫治疗受体CTLA 4和PD-1拮抗。当单独通过T细胞受体刺激时，RCC CD 8（+）TIL在低水平下活化，而加入CD 28共刺激大大增强了活化、功能和增殖。CD 28共刺激重编程RCC CD 8（+）TIL代谢，增加糖酵解和线粒体氧化代谢，可能通过上调GLUT 3。线粒体也融合到更大的程度，具有更高的膜电位和总质量。这些表型依赖于葡萄糖代谢，因为糖酵解抑制剂2-脱氧葡萄糖既防止线粒体的变化，又抑制RCC CD 8（+）TIL的活化和功能。这些数据表明，CD 28共刺激可以通过拯救支持线粒体质量和活性的T细胞糖酵解来恢复RCC CD 8（+）TIL的代谢和功能。
Metabolic reprogramming dictates the fate and function of stimulated T cells, yet these pathways can be suppressed in T cells in tumor microenvironments. We previously showed that glycolytic and mitochondrial adaptations directly contribute to reducing the effector function of renal cell carcinoma (RCC) CD8(+) tumor-infiltrating lymphocytes (TILs). Here we define the role of these metabolic pathways in the activation and effector functions of CD8+ RCC TILs. CD28 costimulation plays a key role in augmenting T cell activation and metabolism, and is antagonized by the inhibitory and checkpoint immunotherapy receptors CTLA4 and PD-1. While RCC CD8(+) TILs were activated at a low level when stimulated through the T cell receptor alone, addition of CD28 costimulation greatly enhanced activation, function, and proliferation. CD28 costimulation reprogrammed RCC CD8(+) TIL metabolism with increased glycolysis and mitochondrial oxidative metabolism, possibly through upregulation of GLUT3. Mitochondria also fused to a greater degree, with higher membrane potential and overall mass. These phenotypes were dependent on glucose metabolism, as the glycolytic inhibitor 2-deoxyglucose both prevented changes to mitochondria and suppressed RCC CD8(+) TIL activation and function. These data show that CD28 costimulation can restore RCC CD8(+) TIL metabolism and function through rescue of T cell glycolysis that supports mitochondrial mass and activity.