Inhibition of UBA6 by inosine augments tumour immunogenicity and responses

Lei Zhang, Li Jiang, Liang Yu, Qin Li, Xiangjun Tian, Jingquan He, Ling Zeng, Yuqin Yang, Chaoran Wang, Yuhan Wei, Xiaoyue Jiang, Jing Li, Xiaolu Ge, Qisheng Gu, Jikun Li, Di Wu, Anthony J. Sadler, Di Yu, Dakang Xu, Yue Gao (), Xiangliang Yuan () and Baokun He ()
Additional contact information
Lei Zhang: Shanghai JiaoTong University School of Medicine
Li Jiang: Shanghai Jiao Tong University School of Medicine
Liang Yu: Shanghai Jiao Tong University School of Medicine
Qin Li: Capital Medical University
Xiangjun Tian: The University of Texas MD Anderson Cancer Center
Jingquan He: Biotree Institute of Health
Ling Zeng: Shanghai JiaoTong University School of Medicine
Yuqin Yang: Shanghai Jiao Tong University School of Medicine
Chaoran Wang: Capital Medical University
Yuhan Wei: Capital Medical University
Xiaoyue Jiang: Capital Medical University
Jing Li: The Affiliated Hospital of Qingdao University
Xiaolu Ge: Shanghai JiaoTong University School of Medicine
Qisheng Gu: Shanghai Jiao Tong University School of Medicine
Jikun Li: Shanghai Jiao Tong University School of Medicine
Di Wu: University of North Carolina at Chapel Hill
Anthony J. Sadler: Hudson Institute of Medical Research
Di Yu: The University of Queensland
Dakang Xu: Shanghai Jiao Tong University School of Medicine
Yue Gao: Beijing Institute of Radiation Medicine
Xiangliang Yuan: Shanghai Jiao Tong University School of Medicine
Baokun He: Shanghai JiaoTong University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33116-z

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