2. Academic Validation
  3. Inhibition of UBA6 by inosine augments tumour immunogenicity and responses

Inhibition of UBA6 by inosine augments tumour immunogenicity and responses

  • Nat Commun. 2022 Sep 15;13(1):5413. doi: 10.1038/s41467-022-33116-z.
Lei Zhang  # 1 2,  Li Jiang  # 3,  Liang Yu  # 4,  Qin Li  # 5,  Xiangjun Tian 6,  Jingquan He 7,  Ling Zeng 1 2,  Yuqin Yang 8,  Chaoran Wang 5,  Yuhan Wei 5,  Xiaoyue Jiang 5,  Jing Li 9,  Xiaolu Ge 1 2,  Qisheng Gu 4,  Jikun Li 4,  Di Wu 10 11,  Anthony J Sadler 12 13,  Di Yu 14,  Dakang Xu 15,  Yue Gao 16,  Xiangliang Yuan 17,  Baokun He 18 19 20
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200080, China.
  • 2 Shanghai Key Laboratory of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
  • 3 Department of Gynecology and Obstetrics, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
  • 4 Department of Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
  • 5 Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
  • 6 Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 7 Biotree Institute of Health, Shanghai, 201800, China.
  • 8 Department of Laboratory Animal Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
  • 9 Department of Clinical Laboratory Science, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, China.
  • 10 Department of Biostatistics, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7455, USA.
  • 11 Department of Periodontology, School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599-7455, USA.
  • 12 Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC, 3168, Australia.
  • 13 Department of Molecular and Translational Science, Monash University, Melbourne, VIC, 3168, Australia.
  • 14 Diamantina Institute, Faculty of Medicine, The University of Queensland, QLD, 4102, Australia.
  • 15 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 16 Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, 100850, China. gaoyue@bmi.ac.cn.
  • 17 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. yuanxiangliang@gmail.com.
  • 18 Department of Gastroenterology, Shanghai General Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200080, China. baokun.he@shgh.cn.
  • 19 Shanghai Key Laboratory of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China. baokun.he@shgh.cn.
  • 20 Institute of Chinese Materia Medica, The Fourth Clinical Medical College, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518033, China. baokun.he@shgh.cn.
  • # Contributed equally.
PMID: 36109526 DOI: 10.1038/s41467-022-33116-z
Abstract

Anti-cancer immunity and response to immune therapy is influenced by the metabolic states of the tumours. Immune checkpoint blockade therapy (ICB) is known to involve metabolic adaptation, however, the mechanism is not fully known. Here we show, by metabolic profiling of plasma samples from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and hence generating an immunologically hotter microenvironment. We find that inosine directly inhibits UBA6 in tumour cells, and lower level of UBA6 makes the tumour more immunogenic and this is reflected in favourable outcome following ICB therapy in human melanomas. Transplanted mouse melanoma and breast Cancer cells with genetic ablation of Uba6 show higher sensitivity to ICB than wild type tumours. Thus, we provide evidence of an inosine-regulated UBA6-dependent pathway governing tumour-intrinsic immunogenicity and hence sensitivity to immune checkpoint inhibition, which might provide targets to overcome ICB resistance.

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