Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses.
Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses.
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DOI：
10.1016/j.cell.2015.08.012
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发表时间：
2015-09-10
期刊：
影响因子：
64.5
通讯作者：
Kaech SM
中科院分区：
文献类型：
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作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
活化的T细胞参与有氧糖酵解和合成代谢，用于生长、增殖和效应功能。我们提出，葡萄糖贫乏的肿瘤微环境限制了肿瘤浸润性T细胞的有氧糖酵解，从而抑制了杀肿瘤效应子功能。我们发现了糖酵解代谢产物磷酸烯醇丙酮酸（PEP）通过抑制sarco/ER Ca 2 +-ATP酶（SERCA）活性在维持T细胞受体介导的Ca 2 +-NFAT信号传导和效应器功能中的新作用。肿瘤特异性CD 4和CD 8 T细胞可以通过磷酸烯醇丙酮酸羧激酶1（PCK 1）的过表达增加PEP的产生来代谢重编程，这增强了效应子功能。此外，PCK 1过表达的T细胞限制了肿瘤的生长，延长了荷黑色素瘤小鼠的存活时间。这项研究揭示了T细胞活性的新代谢检查点，并证明了肿瘤反应性T细胞的代谢重编程可以增强抗肿瘤T细胞反应，从而阐明了免疫治疗的新形式。
Activated T cells engage aerobic glycolysis and anabolic metabolism for growth, proliferation, and effector functions. We propose that a glucose-poor tumor microenvironment limits aerobic glycolysis in tumor-infiltrating T cells, which suppresses tumoricidal effector functions. We discovered a new role for the glycolytic metabolite phosphoenolpyruvate (PEP) in sustaining T cell receptor-mediated Ca2+-NFAT signaling and effector functions by repressing sarco/ER Ca2+-ATPase (SERCA) activity. Tumor-specific CD4 and CD8 T cells could be metabolically reprogrammed by increasing PEP production through overexpression of phosphoenolpyruvate carboxykinase 1 (PCK1), which bolstered effector functions. Moreover, PCK1-overexpressing T cells restricted tumor growth and prolonged the survival of melanoma-bearing mice. This study uncovers new metabolic checkpoints for T cell activity and demonstrates that metabolic reprogramming of tumor-reactive T cells can enhance anti-tumor T cell responses, illuminating new forms of immunotherapy.