Manganese boosts natural killer cell function via cGAS–STING mediated UTX expression

Abstract

Natural killer (NK) cells play a crucial role in both innate immunity and the activation of adaptive immunity. The activating effect of Mn²⁺ on cyclic GMP-AMP(cGAS)–stimulator of interferon genes (STING signaling has been well known, but its effect on NK cells remains elusive. In this study, we identified the vital role of manganese (Mn²⁺) in NK cell activation. Mn²⁺ directly boosts cytotoxicity of NK cells and promotes the cytokine secretion by NK cells, thereby activating CD8+ T cells and enhancing their antitumor activity. Furthermore, Mn²⁺ can simultaneously activate NK-cell intrinsic cGAS and STING and consequently augment the expression of ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX to promote the responsiveness of NK cells. Our results contribute to a broader comprehension of how cGAS–STING regulates NK cells. As a potent agonist of cGAS–STING, Mn²⁺ provides a promising option for NK cell-based immunotherapy of cancers.

Keywords

antitumor immunity / cGAS–STING / manganese / natural killer cells / UTX

References

[1] Mellman I, Chen DS, Powles T, Turley SJ. The cancer-immunity cycle: indication, genotype, and immunotype. Immunity. 2023; 56(10): 2188-2205.

[2] Maskalenko NA, Zhigarev D, Campbell KS. Harnessing natural killer cells for cancer immunotherapy: dispatching the first responders. Nat Rev Drug Discov. 2022; 21(8): 559-577.

[3] Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nat Rev Immunol. 2001; 1(1): 41-49.

[4] Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008; 9(5): 495-502.

[5] Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. Nat Rev Cancer. 2016; 16(1).

[6] Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011; 331(6013): 44-49.

[7] Wolf NK, Kissiov DU, Raulet DH. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol. 2023; 23(2).

[8] Moretta A, Bottino C, Vitale M, et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annu Rev Immunol. 2001; 19: 197-223.

[9] Raulet DH, Gasser S, Gowen BG, Deng W, Jung H. Regulation of ligands for the NKG2D activating receptor. Annu Rev Immunol. 2013; 31: 413-441.

[10] Karlhofer FM, Ribaudo RK, Yokoyama WM. MHC class I alloantigen specificity of Ly-49+ IL-2-activated natural killer cells. Nature. 1992; 358(6381): 66-70.

[11] Kärre K, Ljunggren HG, Piontek G, Kiessling R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature. 1986; 319(6055): 675-678.

[12] Moretta A, Bottino C, Vitale M, et al. Receptors for HLA class-I molecules in human natural killer cells. Annu Rev Immunol. 1996; 14: 619-648.

[13] Raulet DH, Vance RE. Self-tolerance of natural killer cells. Nat Rev Immunol. 2006; 6(7): 520-531.

[14] Sun L, Wu J, Du F, Chen X, Chen ZJ. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013; 339(6121): 786-791.

[15] Woo S-R, Fuertes MB, Corrales L, et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity. 2014; 41(5): 830-842.

[16] Wu J, Sun L, Chen X, et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science. 2013; 339(6121): 826-830.

[17] Woo S-R, Corrales L, Gajewski TF. The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol. 2015; 36(4): 250-256.

[18] Chen Q, Sun L, Chen ZJ. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 2016; 17(10): 1142-1149.

[19] Deng L, Liang H, Xu M, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity. 2014; 41(5): 843-852.

[20] Dou Z, Ghosh K, Vizioli MG, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017; 550(7676): 402-406.

[21] Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009; 461(7265): 788-792.

[22] Mackenzie KJ, Carroll P, Martin C-A, et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature. 2017; 548(7668): 461-465.

[23] Xu MM, Pu Y, Han D, et al. Dendritic cells but not macrophages sense tumor mitochondrial DNA for cross-priming through signal regulatory protein α signaling. Immunity. 2017; 47(2).

[24] Yang Y, Wu M, Cao D, et al. ZBP1-MLKL necroptotic signaling potentiates radiation-induced antitumor immunity via intratumoral STING pathway activation. Sci Adv. 2021; 7(41): eabf6290.

[25] Ablasser A, Goldeck M, Cavlar T, et al. cGAS produces a 2’-5’-linked cyclic dinucleotide second messenger that activates STING. Nature. 2013; 498(7454): 380-384.

[26] Diner EJ, Burdette DL, Wilson SC, et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 2013; 3(5): 1355-1361.

[27] Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008; 455(7213): 674-678.

[28] Sun W, Li Y, Chen L, et al. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Nat Acad Sci USA. 2009; 106(21): 8653-8658.

[29] Zhong B, Yang Y, Li S, et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity. 2008; 29(4): 538-550.

[30] Marcus A, Mao AJ, Lensink-Vasan M, Wang L, Vance RE, Raulet DH. Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity. 2018; 49(4).

[31] Zhang C, Shang G, Gui X, Zhang X, Bai X-C, Chen ZJ. Structural basis of STING binding with and phosphorylation by TBK1. Nature. 2019; 567(7748): 394-398.

[32] Hooy RM, Massaccesi G, Rousseau KE, Chattergoon MA, Sohn J. Allosteric coupling between Mn2+ and dsDNA controls the catalytic efficiency and fidelity of cGAS. Nucleic Acids Res. 2020; 48(8): 4435-4447.

[33] Wang C, Guan Y, Lv M, et al. Manganese increases the sensitivity of the cGAS-STING pathway for double-stranded DNA and is required for the host defense against DNA viruses. Immunity. 2018; 48(4).

[34] Zhao Z, Ma Z, Wang B, Guan Y, Su X-D, Jiang Z. Mn2+ directly activates cGAS and structural analysis suggests Mn2+ induces a noncanonical catalytic synthesis of 2’3’-cGAMP. Cell Rep. 2020; 32(7): 108053.

[35] Horning KJ, Caito SW, Tipps KG, Bowman AB, Aschner M. Manganese is essential for neuronal health. Annu Rev Nutr. 2015; 35: 71-108.

[36] Kwakye GF, Paoliello MMB, Mukhopadhyay S, Bowman AB, Aschner M. Manganese-induced Parkinsonism and Parkinson’s disease: shared and distinguishable features. Int J Environ Res Public Health. 2015; 12(7): 7519-7540.

[37] Waldron KJ, Rutherford JC, Ford D, Robinson NJ. Metalloproteins and metal sensing. Nature. 2009; 460(7257): 823-830.

[38] Zhang K, Qi C, Cai K. Manganese-based tumor immunotherapy. Adv Mater (Deerfield Beach, Fla). 2023; 35(19): e2205409.

[39] Cheng MI, Li JH, Riggan L, et al. The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences. Nat Immunol. 2023; 24(5): 780-791.

[40] McGranahan N, Rosenthal R, Hiley CT, et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell. 2017; 171(6).

[41] Roemer MGM, Advani RH, Redd RA, et al. Classical Hodgkin lymphoma with reduced β2M/MHC class I expression is associated with inferior outcome independent of 9p24.1 status. Cancer Immunol Res. 2016; 4(11): 910-916.

[42] Garrido F, Aptsiauri N, Doorduijn EM, Garcia Lora AM, van Hall T. The urgent need to recover MHC class I in cancers for effective immunotherapy. Curr Opin Immunol. 2016; 39: 44-51.

[43] Tani T, Mathsyaraja H, Campisi M, et al. TREX1 inactivation unleashes cancer cell STING-interferon signaling and promotes antitumor immunity. Cancer Discov. 2024; 14(5): 752-765.

[44] Lv M, Chen M, Zhang R, et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 2020; 30(11): 966-979.

[45] Smialowicz RJ, Rogers RR, Riddle MM, Rowe DG, Luebke RW. In vitro augmentation of natural killer cell activity by manganese chloride. J Toxicol Environ Health. 1986; 19(2): 243-254.

[46] Smialowicz RJ, Riddle MM, Rogers RR, Luebke RW, Burleson GR. Enhancement of natural killer cell activity and interferon production by manganese in young mice. Immunopharmacol Immunotoxicol. 1988; 10(1).

[47] Zhang R, Wang C, Guan Y, et al. Manganese salts function as potent adjuvants. Cell Mol Immunol. 2021; 18(5): 1222-1234.

[48] Wang J, Qu C, Shao X, et al. Carrier-free nanoprodrug for p53-mutated tumor therapy via concurrent delivery of zinc-manganese dual ions and ROS. Bioact Mater. 2023; 20: 404-417.

[49] Jabado N, Jankowski A, Dougaparsad S, Picard V, Grinstein S, Gros P. Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane. J Exp Med. 2000; 192(9): 1237-1248.

[50] Rolny C, Mazzone M, Tugues S, et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell. 2011; 19(1): 31-44.

[51] Nozawa H, Chiu C, Hanahan D. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Nat Acad Sci USA. 2006; 103(33): 12493-12498.

[52] Uhl LFK, Cai H, Oram SL, et al. Interferon-γ couples CD8+ T cell avidity and differentiation during infection. Nat Commun. 2023; 14(1): 6727.

[53] Huseni MA, Wang L, Klementowicz JE, et al. CD8+ T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy. Cell Rep Med. 2023; 4(1): 100878.

[54] Feng W-Q, Zhang Y-C, Xu Z-Q, et al. IL-17A-mediated mitochondrial dysfunction induces pyroptosis in colorectal cancer cells and promotes CD8 + T-cell tumour infiltration. J Transl Med. 2023; 21(1): 335.

[55] Su S, Katopodi X-L, Pita-Juarez YH, Maverakis E, Vlachos IS, Adamopoulos IE. Serine and arginine rich splicing factor 1 deficiency alters pathways involved in IL-17A expression and is implicated in human psoriasis. Clin Immunol (Orlando, Fla). 2022; 240: 109041.

[56] Lu L, Yang C, Zhou X, et al. STING signaling promotes NK cell antitumor immunity and maintains a reservoir of TCF-1+ NK cells. Cell Rep. 2023; 42(9): 113108.

[57] Li Y, Basar R, Wang G, et al. KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape. Nat Med. 2022; 28(10): 2133-2144.

[58] Gong Y, Klein Wolterink RGJ, Wang J, Bos GMJ, Germeraad WTV. Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. J Hematol Oncol. 2021; 14(1): 73.

[59] Hu J, Sánchez-Rivera FJ, Wang Z, et al. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma. Nature. 2023; 616(7958): 806-813.

[60] Luo Z, Liang X, He T, et al. Lanthanide-nucleotide coordination nanoparticles for STING activation. J Am Chem Soc. 2022; 144(36): 16366-16377.

[61] Chen J, Qiu M, Ye Z, et al. In situ cancer vaccination using lipidoid nanoparticles. Sci Adv. 2021; 7(19).

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.