Abstract P2-20-15: Proteolytic regulation of CD73 by TRIM2 orchestrates tumor immunogenicity

Abstract Proteolytic regulation of CD73 by TRIM2 orchestrates tumor immunogenicity Ziyi Fu1,2, Siqi Chen3, Yueming Zhu4, Donghong Zhang4, Ping Xie3, Qiao Jiao4, Shipeng Xu1, Yifan Xue6, Xinhua Lu6, Xinxin Song7, Massimo Cristofanilli8, William J Gradishar3, Kevin Kalinsky5, Yongmei Yin2, Bin Zhang3 and Yong Wan4,5* 1Department of Obstetrics and Gynecology, Department of Pharmacology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, USA. 2Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, China 3Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, USA. 4Department of Pharmacology and Chemical Biology, Winship Cancer Institute, Emory University School of Medicine, USA. 5Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, USA. 6Department of Biomedical Informatics, University of Pittsburgh School of Medicine, USA. 7Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA. 8Department of Medicine, Weill Cornell Medicine, USA. Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint blockade need to be resolved. Here, we report that uncontrolled elevation of CD73 levels due to its aberrant turnover is tightly correlated with poor prognosis in immune-cold triple negative breast cancers (TNBCs), which impedes the efficacy for chemotherapy and immunotherapy. We have identified TRIM21 as a 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. The immunostaining demonstrated the cytosolic colocalization between TRIM21 and CD73. Molecular mapping further identified the amino acid stretches from 340-476 on TRIM21 and residues from 176–224 on CD73 mediated the interaction between TRIM21 and CD73. Replacement of lysine 133, 208, 262 and 321 by arginine on CD73 attenuated CD73 ubiquitylation and degradation. Moreover, TRIM21 is upregulated but CD73 is downregulated in response to IFN- secreted from activated CD8+ T cells in a feedback manner. Importantly, in preclinical animal models, diminishing of CD73 ubiquitylation remarkably promotes tumor growth and impedes antitumor immunity. In addition, a TRIM2hight/CD73low signature in a subgroup of human breast malignancies was associated with a favorable immune profile. Collectively, our findings uncover a novel mechanism that governs CD73 proteolysis and point to a new therapeutic strategy by modulating CD73 ubiquitylation. Citation Format: Ziyi Fu, Yueming Zhu, Kevin Kalinsky, Yong Wan. Proteolytic regulation of CD73 by TRIM2 orchestrates tumor immunogenicity [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-20-15.