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 intr...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.展开更多
The role of IL-17 and IL-17-producing CD4^(+) T cells in acute graft-versus-host disease(GVHD)has been controversial in recent mouse and human studies.We carried out studies in a murine acute GVHD model of fully major...The role of IL-17 and IL-17-producing CD4^(+) T cells in acute graft-versus-host disease(GVHD)has been controversial in recent mouse and human studies.We carried out studies in a murine acute GVHD model of fully major histocompatibility complex-mismatched myeloablative bone marrow transplantation.We showed that donor wild-type CD4^(+) T cells exacerbated acute GVHD compared with IL-17−/−CD4^(+) T cells,while IL-17 reduced the severity of acute GVHD.The augmentation of acute GVHD by transferred donor IL-17-producing CD4^(+) T cells was associated with increased Th1 responses,while IL-17 decreased the percentages of Th1 cells in the GVHD target organs.Furthermore,IL-17 reduced the infiltration of macrophages into the GVHD tissues.In vitro study showed that IL-17 could downregulate Th1 responses,possibly through inhibiting IL-12 production by donor macrophages.Depletion of macrophages in vivo diminished the protective effect of IL-17.Our results demonstrated the differential roles of adoptively transferred donor IL-17-producing CD4^(+) T cells and IL-17 in the same acute GVHD model.展开更多
基金supported by the National Research Foundation Singapore CRP grant(NRF2017NRF-CRP001-034)the start-up grant of National University of Singapore.
文摘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We thank Ziling Zhu of Soochow University for irradiation of the mice. This work has been supported by grants from the National Natural Science Foundation of China (81273268, 81471586, 81273259, 81471589 and 81500145)the Natural Science Foundation of Jiangsu Province (BK20150352)+1 种基金project funding from Suzhou city (SWG0904)and the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘The role of IL-17 and IL-17-producing CD4^(+) T cells in acute graft-versus-host disease(GVHD)has been controversial in recent mouse and human studies.We carried out studies in a murine acute GVHD model of fully major histocompatibility complex-mismatched myeloablative bone marrow transplantation.We showed that donor wild-type CD4^(+) T cells exacerbated acute GVHD compared with IL-17−/−CD4^(+) T cells,while IL-17 reduced the severity of acute GVHD.The augmentation of acute GVHD by transferred donor IL-17-producing CD4^(+) T cells was associated with increased Th1 responses,while IL-17 decreased the percentages of Th1 cells in the GVHD target organs.Furthermore,IL-17 reduced the infiltration of macrophages into the GVHD tissues.In vitro study showed that IL-17 could downregulate Th1 responses,possibly through inhibiting IL-12 production by donor macrophages.Depletion of macrophages in vivo diminished the protective effect of IL-17.Our results demonstrated the differential roles of adoptively transferred donor IL-17-producing CD4^(+) T cells and IL-17 in the same acute GVHD model.
