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Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity

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 ha...

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Autores principales: Fu, Ziyi, Chen, Siqi, Zhu, Yueming, Zhang, Donghong, Xie, Ping, Jiao, Qiao, Chi, Junlong, Xu, Shipeng, Xue, Yifan, Lu, Xinghua, Song, Xinxin, Cristofanilli, Massimo, Gradishar, William J., Kalinsky, Kevin, Yin, Yongmei, Zhang, Bin, Wan, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9821867/
https://www.ncbi.nlm.nih.gov/pubmed/36608132
http://dx.doi.org/10.1126/sciadv.add6626
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author Fu, Ziyi
Chen, Siqi
Zhu, Yueming
Zhang, Donghong
Xie, Ping
Jiao, Qiao
Chi, Junlong
Xu, Shipeng
Xue, Yifan
Lu, Xinghua
Song, Xinxin
Cristofanilli, Massimo
Gradishar, William J.
Kalinsky, Kevin
Yin, Yongmei
Zhang, Bin
Wan, Yong
author_facet Fu, Ziyi
Chen, Siqi
Zhu, Yueming
Zhang, Donghong
Xie, Ping
Jiao, Qiao
Chi, Junlong
Xu, Shipeng
Xue, Yifan
Lu, Xinghua
Song, Xinxin
Cristofanilli, Massimo
Gradishar, William J.
Kalinsky, Kevin
Yin, Yongmei
Zhang, Bin
Wan, Yong
author_sort Fu, Ziyi
collection PubMed
description 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.
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spelling pubmed-98218672023-01-18 Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity Fu, Ziyi Chen, Siqi Zhu, Yueming Zhang, Donghong Xie, Ping Jiao, Qiao Chi, Junlong Xu, Shipeng Xue, Yifan Lu, Xinghua Song, Xinxin Cristofanilli, Massimo Gradishar, William J. Kalinsky, Kevin Yin, Yongmei Zhang, Bin Wan, Yong Sci Adv Biomedicine and Life Sciences 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. American Association for the Advancement of Science 2023-01-06 /pmc/articles/PMC9821867/ /pubmed/36608132 http://dx.doi.org/10.1126/sciadv.add6626 Text en Copyright © 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). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Fu, Ziyi
Chen, Siqi
Zhu, Yueming
Zhang, Donghong
Xie, Ping
Jiao, Qiao
Chi, Junlong
Xu, Shipeng
Xue, Yifan
Lu, Xinghua
Song, Xinxin
Cristofanilli, Massimo
Gradishar, William J.
Kalinsky, Kevin
Yin, Yongmei
Zhang, Bin
Wan, Yong
Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity
title Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity
title_full Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity
title_fullStr Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity
title_full_unstemmed Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity
title_short Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity
title_sort proteolytic regulation of cd73 by trim21 orchestrates tumor immunogenicity
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9821867/
https://www.ncbi.nlm.nih.gov/pubmed/36608132
http://dx.doi.org/10.1126/sciadv.add6626
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