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CD73 expression in normal and pathological human hepatobiliopancreatic tissues

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A Correction to this article was published on 05 February 2019

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Abstract

Background

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.

Results

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.

Conclusions

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.

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  • 05 February 2019

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Abbreviations

ACC:

Acinar cell carcinoma

BilIN:

Bile duct intraepithelial neoplasia

EMT:

Epithelial-to-mesenchymal transition

HIF1:

Hypoxia-inducible factor 1

ICC:

Intrahepatic cholangiocellular carcinoma

IPMN:

Intraductal papillary mucinous neoplasms

MCA:

Mucinous cystadenoma

PDAC:

Pancreatic ductal adenocarcinoma

PanIN:

Pancreatic intraepithelial neoplasia

PanNET:

Pancreatic neuroendocrine tumor

PanNEC:

Pancreatic neuroendocrine tumor and carcinoma

TC:

Tumor cells

TIMC:

Tumor infiltrating mononuclear cells

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Acknowledgements

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.

Funding

This work was supported by the European Community’s Seventh Framework Program (FP7/2007–2013) (under Grant agreement 602200).

Author information

Authors and Affiliations

  1. Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, rue du Bugnon 25, 1011, Lausanne, Switzerland

    Amedeo Sciarra, Inês Monteiro, Benoit Gilbert, Stefano La Rosa, Christine Sempoux & Laurence de Leval

  2. Innovation in Immuno-monitoring and Immunotherapy Platform (PI3), Léon Bérard Cancer Center, Lyon, France

    Christine Ménétrier-Caux & Christophe Caux

  3. Department of Visceral Surgery, Lausanne University Hospital, Lausanne, Switzerland

    Nermin Halkic

  4. Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland

    Pedro Romero

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  1. Amedeo Sciarra
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  2. Inês Monteiro
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  3. Christine Ménétrier-Caux
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  4. Christophe Caux
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  9. Christine Sempoux
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Contributions

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.

Corresponding authors

Correspondence to Christine Sempoux or Laurence de Leval.

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Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

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.

Informed consent

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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Sciarra, A., Monteiro, I., Ménétrier-Caux, C. et al. CD73 expression in normal and pathological human hepatobiliopancreatic tissues. Cancer Immunol Immunother 68, 467–478 (2019). https://doi.org/10.1007/s00262-018-2290-1

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