美国H. Lee莫菲特癌症中心Sungjune Kim课题组的最新研究揭示，抑制Sirt2可增强肿瘤反应性T细胞的代谢适应性和效应因子功能。2020年8月7日，《细胞-代谢》在线发表了这一成果。

研究人员发现NAD⁺依赖性脱乙酰化酶Sirtuin-2（Sirt2）抑制T细胞代谢并损害T细胞效应因子功能。值得注意的是，晚期非小细胞肺癌患者肿瘤浸润淋巴细胞（TIL）中Sirt2的上调与TIL治疗反应呈负相关。从机理上讲，Sirt2通过靶向糖酵解、三羧酸循环、脂肪酸氧化和谷氨酰胺分解过程中的关键酶来抑制T细胞代谢。因此，Sirt2缺陷型小鼠T细胞表现出糖酵解和氧化磷酸化增加，从而增强细胞增殖和效应因子功能，并随后表现出高效的抗肿瘤活性。

重要的是，药物抑制Sirt2使人TIL具有这些有效的代谢适应性和效应因子功能。该研究揭示了Sirt2是重编程T细胞代谢的可操作靶点，其可以广泛增强癌症免疫疗法的效果。

据了解，肿瘤微环境中代谢失调是肿瘤反应性T淋巴细胞适应不良的关键诱导因素。挽救抗肿瘤T细胞效应因子活性的可操作靶点仍有待发现。

附：英文原文

Title: Sirt2 Inhibition Enhances Metabolic Fitness and Effector Functions of Tumor-Reactive T Cells

Author: Imene Hamaidi, Lin Zhang, Nayoung Kim, Min-Hsuan Wang, Cristina Iclozan, Bin Fang, Min Liu, John M. Koomen, Anders E. Berglund, Sean J. Yoder, Jiqiang Yao, Robert W. Engelman, Ben C. Creelan, Jose R. Conejo-Garcia, Scott J. Antonia, James J. Mulé, Sungjune Kim

Issue&Volume: 2020-08-07

Abstract: Dysregulated metabolism is a key driver of maladaptive tumor-reactive T lymphocyteswithin the tumor microenvironment. Actionable targets that rescue the effector activityof antitumor T cells remain elusive. Here, we report that the Sirtuin-2 (Sirt2) NAD+-dependent deacetylase inhibits T cell metabolism and impairs T cell effector functions.Remarkably, upregulation of Sirt2 in human tumor-infiltrating lymphocytes (TILs) negativelycorrelates with response to TIL therapy in advanced non-small-cell lung cancer. Mechanistically,Sirt2 suppresses T cell metabolism by targeting key enzymes involved in glycolysis,tricarboxylic acid-cycle, fatty acid oxidation, and glutaminolysis. Accordingly, Sirt2-deficientmurine T cells exhibit increased glycolysis and oxidative phosphorylation, resultingin enhanced proliferation and effector functions and subsequently exhibiting superiorantitumor activity. Importantly, pharmacologic inhibition of Sirt2 endows human TILswith these superior metabolic fitness and effector functions. Our findings unveilSirt2 as an unexpected actionable target for reprogramming T cell metabolism to augmenta broad spectrum of cancer immunotherapies.

DOI: 10.1016/j.cmet.2020.07.008

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30366-1