Proteolytic regulation of CD73 by TRIM21 orchestrates tumor immunogenicity

被引：22

作者：

Fu, Ziyi ^{[1
,2
]}

Chen, Siqi ^{[3
]}

Zhu, Yueming ^{[4
,5
]}

Zhang, Donghong ^{[4
]}

Xie, Ping ^{[3
]}

Jiao, Qiao ^{[4
]}

Chi, Junlong ^{[1
]}

Xu, Shipeng ^{[1
]}

Xue, Yifan ^{[6
]}

Lu, Xinghua ^{[6
]}

Song, Xinxin ^{[7
]}

Cristofanilli, Massimo ^{[8
]}

Gradishar, William J. ^{[3
]}

Kalinsky, Kevin ^{[5
,9
]}

Yin, Yongmei ^{[2
]}

Zhang, Bin ^{[3
]}

Wan, Yong ^{[4
,5
,9
]}

机构：

[1] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Dept Obstet & Gynecol, Dept Pharmacol,Feinberg Sch Med, Chicago, IL USA

[2] Nanjing Med Univ, Dept Oncol, Affiliated Hosp 1, Nanjing, Peoples R China

[3] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Dept Med, Feinberg Sch Med, Chicago, IL 60208 USA

[4] Emory Univ, Dept Pharmacol & Chem Biol, Sch Med, Atlanta, GA 30322 USA

[5] Emory Univ, Winship Canc Inst, Sch Med, Atlanta, GA 30322 USA

[6] Univ Pittsburgh, Dept Biomed Informat, Sch Med, Pittsburgh, PA USA

[7] UT Southwestern Med Ctr Dallas, Dept Surg, Dallas, TX USA

[8] Weill Cornell Med, Dept Med, New York, NY USA

[9] Emory Univ, Dept Hematol & Med Oncol, Sch Med, Atlanta, GA 30322 USA

来源：

SCIENCE ADVANCES | 2023年 / 9卷 / 01期

关键词：

BREAST-CANCER CELLS; TRIPARTITE MOTIF 22; ECTO-5'-NUCLEOTIDASE CD73; TURNOVER REVEALS; RESPONSE ELEMENT; FAMILY PROTEINS; POOR-PROGNOSIS; EXPRESSION; IMMUNITY; TARGET;

D O I：

10.1126/sciadv.add6626

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Despite the rapid utilization of immunotherapy, emerging challenges to the current immune checkpoint block-ade 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-cata-lyzed 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.

引用

页数：19

共 73 条

[1] Prostaglandin E2-mediated adenosinergic effects on CD14+ cells: Self-amplifying immunosuppression in cancer [J].

Al-Taei, Saly ;

Salimu, Josephine ;

Spary, Lisa K. ;

Clayton, Aled ;

Lester, Jason F. ;

Tabi, Zsuzsanna .

ONCOIMMUNOLOGY, 2017, 6 (02)

[2] CD39 and CD73 in immunity and inflammation [J].

Antonioli, Luca ;

Pacher, Pal ;

Vizi, E. Sylvester ;

Hasko, Gyoergy .

TRENDS IN MOLECULAR MEDICINE, 2013, 19 (06) :355-367

[3]

Aysola K., 2013, Hered. Genet, V2013, DOI 10.4172/2161-1041.S2-001

[4] PROTAC targeted protein degraders: the past is prologue [J].

Bekes, Miklos ;

Langley, David R. ;

Crews, Craig M. .

NATURE REVIEWS DRUG DISCOVERY, 2022, 21 (03) :181-200

[5] Cold Tumors: A Therapeutic Challenge for Immunotherapy [J].

Bonaventura, Paola ;

Shekarian, Tala ;

Alcazer, Vincent ;

Valladeau-Guilemond, Jenny ;

Valsesia-Wittmann, Sandrine ;

Amigorena, Sebastian ;

Caux, Christophe ;

Depil, Stephane .

FRONTIERS IN IMMUNOLOGY, 2019, 10

[6] Regulation of ecto-5′-nucleotidase (CD73) in cultured cortical astrocytes by different inflammatory factors [J].

Brisevac, Dusica ;

Bjelobaba, Ivana ;

Bajic, Aleksandar ;

Clarner, Tim ;

Stojiljkovic, Mirjana ;

Beyer, Cordian ;

Andjus, Pavle ;

Kipp, Markus ;

Nedeljkovic, Nadezda .

NEUROCHEMISTRY INTERNATIONAL, 2012, 61 (05) :681-688

[7] Clinical significance of CD73 in triple-negative breast cancer: multiplex analysis of a phase III clinical trial [J].

Buisseret, L. ;

Pommey, S. ;

Allard, B. ;

Garaud, S. ;

Bergeron, M. ;

Cousineau, I. ;

Ameye, L. ;

Bareche, Y. ;

Paesmans, M. ;

Crown, J. P. A. ;

Di Leo, A. ;

Loi, S. ;

Piccart-Gebhart, M. ;

Willard-Gallo, K. ;

Sotiriou, C. ;

Stagg, J. .

ANNALS OF ONCOLOGY, 2018, 29 (04) :1056-1062

[8] Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden [J].

Chalmers, Zachary R. ;

Connelly, Caitlin F. ;

Fabrizio, David ;

Gay, Laurie ;

Ali, Siraj M. ;

Ennis, Riley ;

Schrock, Alexa ;

Campbell, Brittany ;

Shlien, Adam ;

Chmielecki, Juliann ;

Huang, Franklin ;

He, Yuting ;

Sun, James ;

Tabori, Uri ;

Kennedy, Mark ;

Lieber, Daniel S. ;

Roels, Steven ;

White, Jared ;

Otto, Geoffrey A. ;

Ross, Jeffrey S. ;

Garraway, Levi ;

Miller, Vincent A. ;

Stephens, Phillip J. ;

Frampton, Garrett M. .

GENOME MEDICINE, 2017, 9

[9] Reducing CD73 Expression by IL1β-Programmed Th17 Cells Improves Immunotherapeutic Control of Tumors [J].

Chatterjee, Shilpak ;

Thyagarajan, Krishnamurthy ;

Kesarwani, Pravin ;

Song, Jin H. ;

Soloshchenko, Myroslawa ;

Fu, Jianing ;

Bailey, Stefanie R. ;

Vasu, Chenthamarkshan ;

Kraft, Andrew S. ;

Paulos, Chrystal M. ;

Yu, Xue-Zhong ;

Mehrotra, Shikhar .

CANCER RESEARCH, 2014, 74 (21) :6048-6059

[10] CD73 acts as a prognostic biomarker and promotes progression and immune escape in pancreatic cancer [J].

Chen, Qiangda ;

Pu, Ning ;

Yin, Hanlin ;

Zhang, Jicheng ;

Zhao, Guochao ;

Lou, Wenhui ;

Wu, Wenchuan .

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 2020, 24 (15) :8674-8686

← 1 2 3 4 5 6 7 8 →