SIRT2 Promotes Murine Melanoma Progression Through Natural Killer Cell Inhibition

Abstract

SIRT2, an NAD+-dependent histone deacetylase, has been shown to play a pivotal role in various physiological processes, however, its role in cancer is currently controversial. In recent years, SIRT2 has been described as both a tumor suppressor and oncogene with divergent expression and function in various malignancies. With established roles in inflammation and glucose and iron metabolism, systemic and microenvironment SIRT2, rather than just intrinsic tumor cell expression, might have implications in tumor progression. Moreover, recent interest in the tumor immune microenvironment has further characterized immune cells involved in tumor suppression, including natural killer (NK) cells. Here, we sought to investigate the biological role of systemic SIRT2 in melanoma tumor progression and to evaluate its interaction with key tumor suppressive immune cells.Murine models were employed to investigate the effect of systemic SIRT2 on melanoma tumor progression. Tumor progression was measured in terms of weight and volume for 20 days following subcutaneous inoculation of Sirt2-KI and WT mice with B16-F10 melanoma cells. Differences in tumor-infiltrating immune cell composition were determined by flow cytometry. Granzyme B and Ki-67 immunohistochemical staining was used to measure NK cell functional activity and proliferation in in vivo melanoma samples. NK cell function was further evaluated using in vitro and ex vivo mouse models as well as an in vitro human model. Antibody-mediated NK cell depletion established NK cells as an integral player in SIRT2-mediated tumor promotion. Finally, SIRT2 was pharmacologically inhibited by SirReal2, and the effect on melanoma progression and NK cell tumor infiltration was established.Increased systemic expression of SIRT2 promoted melanoma progression in mice, resulting in larger and heavier tumors. Mechanistically, systemic SIRT2 overexpression reduced the number of tumor-infiltrating NK cells and suppressed NK cell activation and proliferation within the tumor microenvironment. Furthermore, despite the effect of increased tumor growth rate and tumor volume in wild-type littermate mice, NK cell depletion did not affect that in SIRT2-overexpressing mice. Lastly, pharmacological inhibition of SIRT2 increased NK cell tumor infiltration and suppressed melanoma tumor growth.Systemic SIRT2 and NK cell activity exhibit a dynamic functional interaction which promotes melanoma tumor progression. Given the recent renewed interest in NK-cell-mediated immunotherapy response, SIRT2 could represent a new opportunity to mediate immunotherapy response and resistance.