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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Turcotte M,Allard D,Mittal D,Bareche Y,Buisseret L,José V,Pommey S,Delisle V,Loi S,Joensuu H,Kellokumpu-Lehtinen PL,Sotiriou C,Smyth MJ,Stagg Jdoi
10.1158/0008-5472.CAN-17-0707subject
Has Abstractpub_date
2017-10-15 00:00:00pages
5652-5663issue
20eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-17-0707journal_volume
77pub_type
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