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Cancer Res. 2017 Oct 15;77(20):5652-5663. doi: 10.1158/0008-5472.CAN-17-0707. Epub 2017 Aug 30.

CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy.

Author information

1
Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada.
2
Institut du Cancer de Montréal, Montréal, Québec, Canada.
3
Faculté de Pharmacie, Université de Montréal, Québec, Canada.
4
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
5
School of Medicine, University of Queensland, Herston, Queensland, Australia.
6
Molecular Immunology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
7
Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
8
Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
9
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
10
Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
11
Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.
12
Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada. john.stagg@umontreal.ca.

Abstract

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, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ 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. Cancer Res; 77(20); 5652-63. ©2017 AACR.

PMID:
28855210
DOI:
10.1158/0008-5472.CAN-17-0707
[Indexed for MEDLINE]
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