Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.
Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression.
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DOI：
10.1016/j.cell.2015.08.016
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发表时间：
2015-09-10
期刊：
影响因子：
64.5
通讯作者：
Pearce EL
中科院分区：
文献类型：
--
作者：
Chang CH;Qiu J;O'Sullivan D;Buck MD;Noguchi T;Curtis JD;Chen Q;Gindin M;Gubin MM;van der Windt GJ;Tonc E;Schreiber RD;Pearce EJ;Pearce EL
T细胞无法抵御癌症被认为是由于缺乏抗原识别、慢性激活和/或被其他细胞抑制所致。利用小鼠肉瘤模型，我们发现肿瘤消耗的葡萄糖代谢限制了T细胞，导致它们的mTOR活性、糖酵解能力和干扰素-γ的产生受到抑制，从而允许肿瘤进展。我们证明，增强抗原性“退化型”肿瘤的糖酵解足以超过T细胞控制肿瘤生长的保护能力。我们还发现，检查点阻断针对临床使用的CTLA-4、PD-1和PD-L1的抗体，恢复肿瘤中的葡萄糖，允许T细胞糖酵解和干扰素-γ的产生。此外，我们发现，直接阻断肿瘤上的PD-L1通过抑制mTOR活性和减少糖酵解酶的表达来抑制糖酵解，反映了PD-L1在肿瘤葡萄糖利用中的作用。我们的结果证明，肿瘤施加的代谢限制可以在癌症期间调节T细胞的低反应性。
Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic ‘regressor’ tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumors, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.