CD73 expression in normal and pathological human hepatobiliopancreatic tissues
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The tumor-expressed CD73 ectonucleotidase generates immune tolerance and promotes invasiveness via adenosine production from degradation of AMP. While anti-CD73 blockade treatment is a promising tool in cancer immunotherapy, a characterization of CD73 expression in human hepatobiliopancreatic system is lacking.
Patients and methods
CD73 expression was investigated by immunohistochemistry in a variety of non-neoplastic and neoplastic conditions of the liver, pancreas, and biliary tract.
CD73 was expressed in normal hepatobiliopancreatic tissues with subcellular-specific patterns of staining: canalicular in hepatocytes, and apical in cholangiocytes and pancreatic ducts. CD73 was present in all hepatocellular carcinoma (HCC), in all pancreatic ductal adenocarcinoma (PDAC), and in the majority of intra and extrahepatic cholangiocellular carcinomas, whereas it was detected only in a subset of pancreatic neuroendocrine neoplasms and almost absent in acinar cell carcinoma. In addition to the canonical pattern of staining, an aberrant membranous and/or cytoplasmic expression was observed in invasive lesions, especially in HCC and PDAC. These two entities were also characterized by a higher extent and intensity of staining as compared to other hepatobiliopancreatic neoplasms. In PDAC, aberrant CD73 expression was inversely correlated with differentiation (p < 0.01) and was helpful to identify isolated discohesive tumor cells. In addition, increased CD73 expression was associated with reduced overall survival (HR 1.013) and loss of E-Cadherin.
Consistent CD73 expression supports the rationale for testing anti-CD73 therapies in patients with hepatobiliopancreatic malignancies. Specific patterns of expression could also be of help in the routine diagnostic workup.
KeywordsCD73 Cholangiocarcinoma Ecto-5′-nucleotidase Hepatocellular carcinoma Immunohistochemistry Pancreatic carcinoma
Acinar cell carcinoma
Bile duct intraepithelial neoplasia
Hypoxia-inducible factor 1
Intrahepatic cholangiocellular carcinoma
Intraductal papillary mucinous neoplasms
Pancreatic ductal adenocarcinoma
Pancreatic intraepithelial neoplasia
Pancreatic neuroendocrine tumor
Pancreatic neuroendocrine tumor and carcinoma
Tumor infiltrating mononuclear cells
We thank the FP7 European TumAdoR project (Grant 602200), that aims at bringing anti-CD73 mAbs candidates to clinical trial; Prof. Fausto Sessa (Department of Medicine and Surgery, University of Insubria, Varese, Italy) for providing acinar cell carcinoma specimens; Dr. Jerome Pasquier (Institute for Social and Preventive Medicine, Lausanne University Hospital), Dr. sc. Nathalie Piazzon, Dr. sc. Susana Leuba and Mr. Jean-Daniel Roman (Institute of Pathology, Lausanne University Hospital) for their operational support.
AS, IM, BG, NH, and SLR data collection. AS, IM, CS, and LL data analysis. AS, IM, CMC, CC, SLR, PR, CS, and LL drafting. CMC, CC, CS, and LL study design.
This work was supported by the European Community’s Seventh Framework Program (FP7/2007–2013) (under Grant agreement 602200).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
The study protocol was approved by the Vaud cantonal ethics commission on human research (protocol 17/15). All samples were used in accordance with the Declaration of Helsinki.
Patients’ written informed consent was obtained for recent cases (2014–2018). In older cases, the presence of an explicit refusal for the specimen use for research purposes represented an exclusion criterion.
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