Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway
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
Jianwen Chen
Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University, Columbus, United States; Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, United States
Bao Zhao
Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University, Columbus, United States; Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, United States
Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University, Columbus, United States
Tianliang Li
Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University, Columbus, United States
Xiang Cheng
Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University, Columbus, United States; Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, United States
Wang Gong
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, United States
Jing Wang
Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, United States; Department of Cancer Biology and Genetics, The Ohio State University, Columbus, United States
Junran Zhang
Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, United States; Department of Radiation Oncology, The Ohio State University, Columbus, United States
Gang Xin
Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University, Columbus, United States; Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, United States
Yanbao Yu
Department of Chemistry and Biochemistry, University of Delaware, Newark, United States
Yu L Lei
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, United States
Jennifer D Black
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, United States
Zihai Li
Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, United States
Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University, Columbus, United States; Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, United States
The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-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 mice by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt−/−) caused a marked reduction in tumor growth in both syngeneic mice tumor models and a genetic mice colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). 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 Cgas or Sting from Ogt−/− 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.
