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Manganese enhances the antitumor function of CD8+ T cells by inducing type I interferon production

Cellular & Molecular Immunology volume 18, pages 1571–1574 (2021)Cite this article

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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.

To investigate the immunoregulatory functions of Mn2+ during tumor development, we performed flow cytometry analysis of immune cells from the liver and spleen of tumor-bearing mice. The percentages of CD4+ T and CD8+ T cells were slightly decreased in the spleen after MnCl2 treatment (Supplementary Fig. 2a). However, in the tumor-bearing liver, the percentage of CD8+ T cells showed an increasing trend upon MnCl2 treatment. The percentage of DCs was increased in the spleen and liver upon MnCl2 treatment. The activation (CD69 expression) of CD4+ T cells and CD8+ T cells was also upregulated in the spleen and liver of MnCl2-treated tumor-bearing mice (Fig. 1b). Although the percentage of effector T cells was not affected (Supplementary Fig. 2b, c), IFN-γ and TNF-α production by CD8+ T cells from the spleen or tumor-bearing liver of MnCl2-treated mice displayed significant increases compared with that by CD8+ T cells from the same organs of control mice (Fig. 1c, d). Mn2+ did not affect the TNF-α or IFN-γ production of CD4+ T cells from the spleen or tumor-bearing liver (Supplementary Fig. 3a). A recent study with nanoparticles acting as both drug carriers and Mn2+ generators demonstrated that Mn2+ enhanced cGAS-STING activity and upregulated the production of TNF-α and IL-6.6 Moreover, TNF-α has been found to be essential for the therapeutic efficacy of cyclic dinucleotide STING agonists in nonimmunogenic tumors.7 Therefore, IFN-γ and TNF-α could be the critical effector molecules produced by T cells downstream of type I IFN during the antitumor immune response. To determine whether Mn2+ can directly affect cytokine production by T cells, we isolated T cells from the liver and spleen of tumor-bearing mice and then treated these cells with MnCl2 for 3 days in the presence of anti-CD3 and anti-CD28 antibodies (Supplementary Fig. 3b). There was no significant difference in the production of TNF-α and IFN-γ by CD4+ T cells or CD8+ T cells between the MnCl2-treated and control groups. These results suggest that MnCl2 does not directly affect cytokine production by T cells and that the increased cytokine production by CD8+ T cells induced by MnCl2 is mediated through other immune mechanisms.

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Fig. 1: Mn2+ inhibited tumor growth by promoting the antitumor function of CD8+ T cells in a type I IFN-dependent manner in a murine orthotopic HCC model

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Acknowledgements

This work was supported by the National Research Foundation Singapore CRP grant (NRF2017NRF-CRP001–034) and the start-up grant of National University of Singapore. We thank Mr. Teo Guohui and Dr. Paul Edward Hutchinson for assistance with flow cytometry.

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  1. Mengze Lv

    Present address: Jill Roberts Institute for Research in Inflammatory Bowel Disease (JRI), Weill Cornell Medicine, Cornell University, New York, NY, USA

  2. These authors contributed equally: Yuan Song, Yonghao Liu

Authors and Affiliations

  1. Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117456, Singapore

    Yuan Song, Yonghao Liu, Huey Yee Teo, Zuhairah Binte Hanafi, Yu Mei, Ying Zhu, Yen Leong Chua & Haiyan Liu

  2. Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, 100871, China

    Mengze Lv & Zhengfan Jiang

  3. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China

    Mengze Lv & Zhengfan Jiang

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Contributions

Y.S., Y.L., and H.L. designed the research. Y.S. and Y.L. performed the experiments. H.Y.T., Z.B.H., Y.M., Y.Z., and C.Y.L. assisted in the experiments. M.L. and Z.J. assisted in the data interpretation. Y.S. and H.L. analyzed the data and wrote the manuscript.

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Correspondence to Haiyan Liu.

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Song, Y., Liu, Y., Teo, H.Y. et al. Manganese enhances the antitumor function of CD8+ T cells by inducing type I interferon production. Cell Mol Immunol 18, 1571–1574 (2021). https://doi.org/10.1038/s41423-020-00524-4

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