Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity

Author:

Fu Ziyi12ORCID,Chen Siqi3ORCID,Zhu Yueming45ORCID,Zhang Donghong4ORCID,Xie Ping3ORCID,Jiao Qiao4ORCID,Chi Junlong1ORCID,Xu Shipeng1,Xue Yifan6ORCID,Lu Xinghua6ORCID,Song Xinxin7,Cristofanilli Massimo8ORCID,Gradishar William J.3,Kalinsky Kevin59,Yin Yongmei2ORCID,Zhang Bin3ORCID,Wan Yong459ORCID

Affiliation:

1. Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

2. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

3. Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

4. Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.

5. Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA.

6. Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

7. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.

8. Department of Medicine, Weill Cornell Medicine, New York, NY, USA.

9. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA.

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 TRIM21 high /CD73 low 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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