Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 27, Pages 11091-11096Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1222251110
Keywords
ectonucleotidase; immunogenic cell death; immunotherapy
Categories
Funding
- Susan G. Komen for the Cure [IIR12221504]
- National Health and Medical Research Council of Australia [1013667, 1007902]
- Victorian Cancer Agency [EOI09_71]
- Canadian Institutes of Health Research
- Cancer Research Society of Canada
- National Health and Medical Research Council
- Fonds J. C. Heuson
- National Health and Medical Research Council Career Development Award 2 award
- National Health and Medical Research Council Australia Fellowship [628623]
- Famille Jean-Guy Sabourin Research Chair of University of Montreal
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Using gene-expression data from over 6,000 breast cancer patients, we report herein that high CD73 expression is associated with a poor prognosis in triple-negative breast cancers (TNBC). Because anthracycline-based chemotherapy regimens are standard treatment for TNBC, we investigated the relationship between CD73 and anthracycline efficacy. In TNBC patients treated with anthracycline-only preoperative chemotherapy, high CD73 gene expression was significantly associated with a lower rate of pathological complete response or the disappearance of invasive tumor at surgery. Using mouse models of breast cancer, we demonstrated that CD73 overexpression in tumor cells conferred chemoresistance to doxorubicin, a commonly used anthracycline, by suppressing adaptive antitumor immune responses via activation of A2A adenosine receptors. Targeted blockade of CD73 enhanced doxorubicin-mediated antitumor immune responses and significantly prolonged the survival of mice with established metastatic breast cancer. Taken together, our data suggest that CD73 constitutes a therapeutic target in TNBC.
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