Editors' ChoiceCancer

Sirt2: A master regulator of T cell metabolism?

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Science Translational Medicine  26 Aug 2020:
Vol. 12, Issue 558, eabd6009
DOI: 10.1126/scitranslmed.abd6009

Abstract

Sirt2 controls metabolic fitness and antitumor function of T cells.

A fierce metabolic tug of war exists between tumor-infiltrating lymphocytes (TILs) and tumor cells due to their parallel metabolic rewiring and the competition created by the nutrient-poor tumor microenvironment (TME). Consequently, metabolic fitness of TILs, defined as the ability to compete for the limited amount of metabolic fuels in the TME, largely determines T cell antitumor function. Thus, it is important to identify master regulators of metabolic fitness that can enhance TIL function and serve as targets for cancer immunotherapy.

Sirtuins are nicotinamide adenine dinucleotide (NAD+)–dependent deacetylases. By modulating protein acetylation, sirtuins have a key role in cell metabolism, as many metabolic enzymes undergo acetylation to gain full activity. To explore the involvement of a specific sirtuin, Sirt2, in T cell metabolism and antitumor immunity, Hamaidi et al. characterized Sirt2 expression in patients with non-small cell lung cancer (NSCLC) after TIL therapy and observed Sirt2 up-regulation only in TILs from nonresponder patients. When isolated TILs from patients with NSCLC were cocultured with autologous tumor cells, Sirt2 inhibition enhanced cytotoxicity, suggesting that Sirt2 acts as an immune checkpoint in TILs. The authors confirmed this in a series of elegant mouse studies, which collectively showed that Sirt2−/− T cells exhibit greater proliferation, survival, and effector function as measured by interferon-γ production and cytotoxicity. Upon transfer into tumor-bearing mice lacking endogenous T cells, tumor antigen–specific Sirt2−/− T cells potently suppressed lung metastases as compared to their wild-type counterparts. Mechanistically, Sirt2 deficiency enhanced the acetylation and activity of many key enzymes involved in glycolysis, glutaminolysis, fatty acid oxidation, and oxidative phosphorylation and thereby augmented the overall metabolic fitness of T cells and promoted antitumor immunity. Notably, the hypermetabolic phenotype of Sirt2−/− T cells did not depend on commonly recognized master regulators of cell metabolism.

Taken together, these results identify Sirt2 as a new master regulator of cell metabolism. Inhibition of Sirt2 may represent a promising approach to boost antitumor immunity. However, before the bench-to-bedside transition, further systemic in vivo testing of Sirt2 inhibition is warranted. Because the researchers used germline Sirt2−/− mice, the impact of Sirt2 deficiency on other immune and nonimmune cells cannot be ruled out. For the same reason, the efficacy of combined Sirt2 inhibition and immunotherapy should be further evaluated.

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