Inhibition of UBA6 by Inosine Augments Tumour Immunogenicity and Responses

Authors

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
Baokun He

Publication Date

9-15-2022

Journal

Nature Communications

DOI

10.1038/s41467-022-33116-z

PMID

36109526

PMCID

PMC9478149

PubMedCentral® Posted Date

9-15-2022

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, Combined Modality Therapy, Humans, Immune Checkpoint Inhibitors, Inosine, Melanoma, Mice, Radioimmunotherapy, Tumor Microenvironment, Ubiquitin-Activating Enzymes, Cancer metabolism, Cancer immunotherapy, Immunoediting, Ubiquitylation

Published Open-Access

yes

Recommended Citation

Zhang, Lei; Jiang, Li; Yu, Liang; et al., "Inhibition of UBA6 by Inosine Augments Tumour Immunogenicity and Responses" (2022). Faculty, Staff and Student Publications. 4424.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4424