CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors
CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors
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cd36介导的代谢适应支持肿瘤中调节性T细胞的存活和功能
DOI：
10.1038/s41590-019-0589-5
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发表时间：
2020-02-17
影响因子：
30.5
通讯作者：
Ho, Ping-Chih
中科院分区：
文献类型：
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作者：
Wang, Haiping;Franco, Fabien;Ho, Ping-Chih
耗尽调节性T细胞（T-reg细胞）以抵消肿瘤微环境（TME）的免疫抑制特征是癌症治疗的一种有吸引力的策略;然而，由于其抑制功能的全身性损害而导致的自身免疫限制了其治疗潜力。阐明特异性破坏肿瘤内T-reg细胞的方法是癌症免疫治疗迫切需要的。我们发现，CD 36选择性上调肿瘤内的T-reg细胞作为一个中央代谢调节。CD 36通过过氧化物酶体增殖物激活受体β信号转导微调线粒体适应性，编程T-reg细胞以适应富含乳酸的TME。在T-reg细胞中的Cd 36基因消融抑制肿瘤生长，伴随着肿瘤内T-reg细胞的减少和肿瘤浸润淋巴细胞中抗肿瘤活性的增强，而不破坏免疫稳态。此外，CD 36靶向与抗程序性细胞死亡蛋白1治疗一起引发了相加的抗肿瘤应答。我们的研究结果揭示了未探索的代谢适应，协调肿瘤内T-reg细胞的生存和功能，以及靶向这一途径重编程TME的治疗潜力。Ho及其同事报告说，肿瘤浸润性调节性T细胞通过上调CD 36的表达来适应这种肿瘤环境，这使它们能够使用脂肪酸来促进其代谢。
Depleting regulatory T cells (T-reg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T-reg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral T-reg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-beta signaling, programming T-reg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T-reg cells suppressed tumor growth accompanied by a decrease in intratumoral T-reg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral T-reg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.Tumor environments are highly acidic due to high concentrations of lactic acid. Ho and colleagues report that tumor-infiltrating regulatory T cells adapt to this tumor environment by upregulating expression of CD36, which allows them to use fatty acids to fuel their metabolism.