Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity

• Type of Material: Article
• Authors: Ziyi Fu, Northwestern University; Siqi Chen, Northwestern University; Yueming Zhu, Emory University; Donghong Zhang, Emory University; Ping Xie, Northwestern University; Qiao Jiao, Emory University; Junlong Chi, Northwestern University; Shipeng Xu, Northwestern University; Yifan Xue, University of Pittsburgh; Xinghua Lu, University of Pittsburgh; Xinxin Song, UT Southwestern Medical Center, Dallas; Massimo Cristofanilli, Weill Cornell Medicine; William J Gradishar, Northwestern University; Kevin Kalinsky, Emory University; Yongmei Yin, Nanjing Medical University; Bin Zhang, Northwestern University Feinberg; Yong Wan, Emory University
• Language: English
• Date: 2023-01-06
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.add6626
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 9
• Issue: 1
• Start Page: eadd6626
• End Page: eadd6626
• Grant/Funding Information: This work was supported by NIH R01CA258857, NIH R01CA258765, NIH R01CA250110, and NIH R01CA202948. This work was also partially supported by Northwestern University Friends of Prentice Award SP0052611.
• Keywords: Science & Technology - Other Topics; IMMUNITY; ECTO-5'-NUCLEOTIDASE CD73; FAMILY PROTEINS; Science & Technology; RESPONSE ELEMENT; BREAST-CANCER CELLS; EXPRESSION; POOR-PROGNOSIS; TARGET; Multidisciplinary Sciences; TRIPARTITE MOTIF 22; TURNOVER REVEALS
• Research Categories: Health Sciences, Oncology

Abstract

Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that elevation of CD73 levels due to its aberrant turnover is correlated with poor prognosis in immune-cold triple-negative breast cancers (TNBCs). We have identified TRIM21 as an E3 ligase that governs CD73 destruction. Disruption of TRIM21 stabilizes CD73 that in turn enhances CD73-catalyzed production of adenosine, resulting in the suppression of CD8+ T cell function. Replacement of lysine 133, 208, 262, and 321 residues by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM21high/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation.