摘要
The presence of cytosolic DNA at tumor sites and the activation of the cGAS-STING pathway have been implicated in the activation of antitumor immune responses.1,2,3 Manganese (Mn) is a necessary trace element for intracellular activities. It plays important roles in development, digestion, reproduction, antioxidant defense, energy production, immunity, and neuronal activity regulation.4 Mn was reported to enhance cGAS-STING activation through increased sensitivity to dsDNA during viral infections.5 However, it is unclear whether Mn can enhance antitumor immune functions. Here, we revealed that Mn2+ could inhibit the development of murine hepatocellular carcinoma (HCC) through immune modulations. It upregulated IFN-γ and TNF-α production in splenic and tumor-infiltrating CD8+ T cells. Moreover, Mn2+ significantly increased type I interferon (IFN) production and type I IFN-stimulated gene (ISG) expression in tumor-bearing mice. Further analysis revealed that myeloid cells could upregulate type I IFN production and increase costimulatory molecule expression upon Mn2+ stimulation. In vivo depletion of CD8+ T cells or treatment of IFNAR KO mice diminished the antitumor activity of Mn2+, suggesting that the antitumor function of Mn2+ is dependent on both CD8+ T cells and type I IFN signaling. Our results provide evidence to support Mn2+ as a novel agent that can be incorporated into cancer immunotherapy.
基金
supported by the National Research Foundation Singapore CRP grant(NRF2017NRF-CRP001-034)
the start-up grant of National University of Singapore.
