CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

被引：95

作者：

Turcotte, Martin ^{[1
,2
,3
]}

Allard, David ^{[1
,2
,3
]}

Mittal, Deepak ^{[4
,5
]}

Bareche, Yacine ^{[6
,7
]}

Buisseret, Laurence ^{[6
,7
]}

Jose, Vinu ^{[6
,7
]}

Pommey, Sandra ^{[1
,2
,3
]}

Delisle, Vincent ^{[1
,2
,3
]}

Loi, Sherene ^{[8
,9
]}

Joensuu, Heikki ^{[10
,11
]}

Kellokumpu-Lehtinen, Pirkko-Liisa ^{[12
]}

Sotiriou, Christos ^{[6
,7
]}

Smyth, Mark J. ^{[4
,5
]}

Stagg, John ^{[1
,2
,3
]}

机构：

[1] Ctr Hosp Univ Montreal, Ctr Rech, 900 St Denis St,R10-428, Montreal, PQ H2X 0A9, Canada

[2] Inst Canc Montreal, Montreal, PQ, Canada

[3] Univ Montreal, Fac Pharm, Montreal, PQ, Canada

[4] QIMR Berghofer Med Res Inst, Immunol Canc & Infect Lab, Herston, Qld, Australia

[5] Univ Queensland, Sch Med, Herston, Qld, Australia

[6] Univ Libre Bruxelles, Mol Immunol Unit, Inst Jules Bordet, Brussels, Belgium

[7] Univ Libre Bruxelles, Breast Canc Translat Res Lab JC Heuson, Inst Jules Bordet, Brussels, Belgium

[8] Peter MacCallum Canc Ctr, Canc Immunol Program, East Melbourne, Vic, Australia

[9] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia

[10] Helsinki Univ Hosp, Helsinki, Finland

[11] Univ Helsinki, Helsinki, Finland

[12] Univ Tampere, Fac Med & Life Sci, Tampere, Finland

来源：

CANCER RESEARCH | 2017年 / 77卷 / 20期

基金：

英国医学研究理事会;

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; TUMOR-INFILTRATING LYMPHOCYTES; HER2-POSITIVE BREAST-CANCER; GROWTH-FACTOR-BETA; RECEPTOR EXPRESSION; POOR-PROGNOSIS; ADENOSINE; TRASTUZUMAB; ECTO-5'-NUCLEOTIDASE; CHEMOTHERAPY;

D O I：

10.1158/0008-5472.CAN-17-0707

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2-driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFb genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible- factor (HIF)-1 gene signature. Human mammary cells treated with TGFb or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. (C) 2017 AACR.

引用

页码：5652 / 5663

页数：12

共 43 条

[1] Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs [J].