Inhibition of -GlcNAc Transferase Activates Type I Interferon-dependent Antitumor Immunity by Bridging CGAS-STING Pathway

Overview

Journal bioRxiv

Date 2024 Jan 3

PMID 38168435

Authors

Jianwen Chen

Bao Zhao

Hong Dong

TianLiang Li

Xiang Cheng

Wang Gong

Jing Wang

Junran Zhang

Gang Xin

Yanbao Yu

Yu L Lei

Jennifer D Black

Zihai Li

Haitao Wen

Affiliations

Soon will be listed here.

Abstract

The -GlcNAc transferase (OGT) is an essential enzyme that mediates protein -GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and -GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT ( ) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the gene ( ). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of or from cancer cells restored tumor growth, and this correlated with impaired CD8 T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.

References

Shen Y, Bert N, Chitre A, Koo C, Nga X, Ho S . Genome-derived cytosolic DNA mediates type I interferon-dependent rejection of B cell lymphoma cells. Cell Rep. 2015; 11(3):460-73. DOI: 10.1016/j.celrep.2015.03.041. View

Li S, Kong L, Meng Y, Cheng C, Lemacon D, Yang Z . Cytosolic DNA sensing by cGAS/STING promotes TRPV2-mediated Ca release to protect stressed replication forks. Mol Cell. 2023; 83(4):556-573.e7. PMC: 9974760. DOI: 10.1016/j.molcel.2022.12.034. View

Liu Y, Liu H, Yu T, Lu Q, Zhang F, Liu G . O-GlcNAcylation of MORC2 at threonine 556 by OGT couples TGF-β signaling to breast cancer progression. Cell Death Differ. 2022; 29(4):861-873. PMC: 8991186. DOI: 10.1038/s41418-021-00901-0. View

Deng L, Liang H, Xu M, Yang X, Burnette B, Arina A . STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors. Immunity. 2014; 41(5):843-52. PMC: 5155593. DOI: 10.1016/j.immuni.2014.10.019. View

Li T, Chen Z . The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med. 2018; 215(5):1287-1299. PMC: 5940270. DOI: 10.1084/jem.20180139. View

Olivier-Van Stichelen S, Guinez C, Mir A, Perez-Cervera Y, Liu C, Michalski J . The hexosamine biosynthetic pathway and O-GlcNAcylation drive the expression of β-catenin and cell proliferation. Am J Physiol Endocrinol Metab. 2011; 302(4):E417-24. DOI: 10.1152/ajpendo.00390.2011. View

Gui X, Yang H, Li T, Tan X, Shi P, Li M . Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature. 2019; 567(7747):262-266. PMC: 9417302. DOI: 10.1038/s41586-019-1006-9. View

Gluck S, Guey B, Gulen M, Wolter K, Kang T, Schmacke N . Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol. 2017; 19(9):1061-1070. PMC: 5826565. DOI: 10.1038/ncb3586. View

Xu M, Pu Y, Han D, Shi Y, Cao X, Liang H . Dendritic Cells but Not Macrophages Sense Tumor Mitochondrial DNA for Cross-priming through Signal Regulatory Protein α Signaling. Immunity. 2017; 47(2):363-373.e5. PMC: 5564225. DOI: 10.1016/j.immuni.2017.07.016. View

10.

Ghosh M, Saha S, Bettke J, Nagar R, Parrales A, Iwakuma T . Mutant p53 suppresses innate immune signaling to promote tumorigenesis. Cancer Cell. 2021; 39(4):494-508.e5. PMC: 8044023. DOI: 10.1016/j.ccell.2021.01.003. View

11.

Li X, Gong W, Wang H, Li T, Attri K, Lewis R . O-GlcNAc Transferase Suppresses Inflammation and Necroptosis by Targeting Receptor-Interacting Serine/Threonine-Protein Kinase 3. Immunity. 2019; 50(3):576-590.e6. PMC: 6426684. DOI: 10.1016/j.immuni.2019.01.007. View

12.

Ortiz-Meoz R, Jiang J, Lazarus M, Orman M, Janetzko J, Fan C . A small molecule that inhibits OGT activity in cells. ACS Chem Biol. 2015; 10(6):1392-7. PMC: 4475500. DOI: 10.1021/acschembio.5b00004. View

13.

Takagi T, Naito Y, Uchiyama K, Suzuki T, Hirata I, Mizushima K . Carbon monoxide liberated from carbon monoxide-releasing molecule exerts an anti-inflammatory effect on dextran sulfate sodium-induced colitis in mice. Dig Dis Sci. 2010; 56(6):1663-71. DOI: 10.1007/s10620-010-1484-y. View

14.

Brahmer J, Tykodi S, Chow L, Hwu W, Topalian S, Hwu P . Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366(26):2455-65. PMC: 3563263. DOI: 10.1056/NEJMoa1200694. View

15.

Yang H, Wang H, Ren J, Chen Q, Chen Z . cGAS is essential for cellular senescence. Proc Natl Acad Sci U S A. 2017; 114(23):E4612-E4620. PMC: 5468617. DOI: 10.1073/pnas.1705499114. View

16.

Yost K, Satpathy A, Wells D, Qi Y, Wang C, Kageyama R . Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat Med. 2019; 25(8):1251-1259. PMC: 6689255. DOI: 10.1038/s41591-019-0522-3. View

17.

Young K, Morrison H . Quantifying Microglia Morphology from Photomicrographs of Immunohistochemistry Prepared Tissue Using ImageJ. J Vis Exp. 2018; (136). PMC: 6103256. DOI: 10.3791/57648. View

18.

Joffre O, Segura E, Savina A, Amigorena S . Cross-presentation by dendritic cells. Nat Rev Immunol. 2012; 12(8):557-69. DOI: 10.1038/nri3254. View

19.

Guan J, Lu C, Jin Q, Lu H, Chen X, Tian L . MLH1 Deficiency-Triggered DNA Hyperexcision by Exonuclease 1 Activates the cGAS-STING Pathway. Cancer Cell. 2020; 39(1):109-121.e5. PMC: 8666006. DOI: 10.1016/j.ccell.2020.11.004. View

20.

Liu S, Cai X, Wu J, Cong Q, Chen X, Li T . Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015; 347(6227):aaa2630. DOI: 10.1126/science.aaa2630. View