Cancer Immunology, Immunotherapy

, Volume 68, Issue 3, pp 467–478 | Cite as

CD73 expression in normal and pathological human hepatobiliopancreatic tissues

  • Amedeo Sciarra
  • Inês Monteiro
  • Christine Ménétrier-Caux
  • Christophe Caux
  • Benoit Gilbert
  • Nermin Halkic
  • Stefano La Rosa
  • Pedro Romero
  • Christine SempouxEmail author
  • Laurence de LevalEmail author
Original Article



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.


CD73 Cholangiocarcinoma Ecto-5′-nucleotidase Hepatocellular carcinoma Immunohistochemistry Pancreatic carcinoma 



Acinar cell carcinoma


Bile duct intraepithelial neoplasia


Epithelial-to-mesenchymal transition


Hypoxia-inducible factor 1


Intrahepatic cholangiocellular carcinoma


Intraductal papillary mucinous neoplasms


Mucinous cystadenoma


Pancreatic ductal adenocarcinoma


Pancreatic intraepithelial neoplasia


Pancreatic neuroendocrine tumor


Pancreatic neuroendocrine tumor and carcinoma


Tumor cells


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.

Author 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.


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.

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.

Supplementary material

262_2018_2290_MOESM1_ESM.pdf (1.8 mb)
Supplementary material 1 (PDF 1817 KB)


  1. 1.
    Sciarra A, Monteiro I, Ménétrier-Caux C, Caux C, La Rosa S, Romero P, Sempoux C, de Leval L (2018) CD73 in hepatobiliopancreatic system: a potential target for immunotherapy and additional tool for the pathological diagnosis. Virchows Arch 473(Suppl. 1):S124 (Poster 014 PS114 Abstract)Google Scholar
  2. 2.
    Zimmermann H, Zebisch M, Strater N (2012) Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 8(3):437–502Google Scholar
  3. 3.
    Thomson L, Ruedi J, Glass A, Moldenhauer G, Moller P, Low M, Klemens M, Massaia M, Lucas A: Production and characterization of monoclonal antibodies to the glycosyl phosphatidylinositol-anchored lymphocyte differentiation antigen ecto-5′-nucleotidase (CD73). HLA 1990, 35(1):9–19Google Scholar
  4. 4.
    Wu C, Jin X, Tsueng G, Afrasiabi C, Su AI (2016) BioGPS: building your own mash-up of gene annotations and expression profiles. Nucleic Acids Res 44(D1):D313–D316Google Scholar
  5. 5.
    Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, Zhang J, Soden R, Hayakawa M, Kreiman G et al (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 101(16):6062–6067Google Scholar
  6. 6.
    Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A et al: Proteomics. Tissue-based map of the human proteome. Science 2015, 347(6220):1260419Google Scholar
  7. 7.
    Antonioli L, Yegutkin GG, Pacher P, Blandizzi C, Haskó G (2016) Anti-CD73 in cancer immunotherapy: awakening new opportunities. Trends Cancer 2(2):95–109Google Scholar
  8. 8.
    Colgan SP, Eltzschig HK, Eckle T, Thompson LF (2006) Physiological roles for ecto-5′-nucleotidase (CD73). Purinergic Signal 2(2):351–360Google Scholar
  9. 9.
    Haskó G, Linden J, Cronstein B, Pacher P (2008) Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 7(9):759–770Google Scholar
  10. 10.
    Sadej R, Skladanowski AC (2012) Dual, enzymatic and non-enzymatic, function of ecto-5′-nucleotidase (eN, CD73) in migration and invasion of A375 melanoma cells. Acta Biochim Pol 59(4):647–652Google Scholar
  11. 11.
    Gao ZW, Wang HP, Lin F, Wang X, Long M, Zhang HZ, Dong K (2017) CD73 promotes proliferation and migration of human cervical cancer cells independent of its enzyme activity. BMC Cancer 17(1):135Google Scholar
  12. 12.
    Wang L, Fan J, Thompson LF, Zhang Y, Shin T, Curiel TJ, Zhang B (2011) CD73 has distinct roles in nonhematopoietic and hematopoietic cells to promote tumor growth in mice. J Clin Investig 121(6):2371–2382Google Scholar
  13. 13.
    Antonioli L, Pacher P, Vizi ES, Hasko G (2013) CD39 and CD73 in immunity and inflammation. Trends Mol Med 19(6):355–367Google Scholar
  14. 14.
    Bono MR, Fernández D, Flores-Santibáñez F, Rosemblatt M, Sauma D (2015) CD73 and CD39 ectonucleotidases in T cell differentiation: beyond immunosuppression. FEBS Lett 589(22):3454–3460Google Scholar
  15. 15.
    Zhang B, Song B, Wang X, Chang XS, Pang T, Zhang X, Yin K, Fang GE (2015) The expression and clinical significance of CD73 molecule in human rectal adenocarcinoma. Tumour Biol 36(7):5459–5466Google Scholar
  16. 16.
    Zhi X, Wang Y, Yu J, Yu J, Zhang L, Yin L, Zhou P (2012) Potential prognostic biomarker CD73 regulates epidermal growth factor receptor expression in human breast cancer. IUBMB Life 64(11):911–920Google Scholar
  17. 17.
    Wu XR, He XS, Chen YF, Yuan RX, Zeng Y, Lian L, Zou YF, Lan N, Wu XJ, Lan P (2012) High expression of CD73 as a poor prognostic biomarker in human colorectal cancer. J Surg Oncol 106(2):130–137Google Scholar
  18. 18.
    Xu S, Shao QQ, Sun JT, Yang N, Xie Q, Wang DH, Huang QB, Huang B, Wang XY, Li XG et al (2013) Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas. Neuro Oncol 15(9):1160–1172Google Scholar
  19. 19.
    Kondo T, Nakazawa T, Murata SI, Katoh R (2006) Expression of CD73 and its ecto-5′-nucleotidase activity are elevated in papillary thyroid carcinomas. Histopathology 48(5):612–614Google Scholar
  20. 20.
    Stella J, Bavaresco L, Braganhol E, Rockenbach L, Farias PF, Wink MR, Azambuja AA, Barrios CH, Morrone FB Oliveira Battastini AM(2010) Differential ectonucleotidase expression in human bladder cancer cell lines. Urol Oncol 28(3):260–267Google Scholar
  21. 21.
    Oh HK, Sin JI, Choi J, Park SH, Lee TS, Choi YS (2012) Overexpression of CD73 in epithelial ovarian carcinoma is associated with better prognosis, lower stage, better differentiation and lower regulatory T cell infiltration. J Gynecol Oncol 23(4):274–281Google Scholar
  22. 22.
    Yang Q, Du J, Zu L (2013) Overexpression of CD73 in prostate cancer is associated with lymph node metastasis. Pathol Oncol Res 19(4):811–814Google Scholar
  23. 23.
    Turcotte M, Spring K, Pommey S, Chouinard G, Cousineau I, George J, Chen GM, Gendoo DM, Haibe-Kains B, Karn T et al (2015) CD73 is associated with poor prognosis in high-grade serous ovarian cancer. Cancer Res 75(21):4494–4503Google Scholar
  24. 24.
    Leclerc BG, Charlebois R, Chouinard G, Allard B, Pommey S, Saad F, Stagg J (2016) CD73 expression is an independent prognostic factor in prostate cancer. Clin Cancer Res 22(1):158–166Google Scholar
  25. 25.
    Gao ZW, Dong K, Zhang HZ: The roles of CD73 in cancer. BioMed Res Int 2014, 2014:460654Google Scholar
  26. 26.
    Wang H, Lee S, Nigro CL, Lattanzio L, Merlano M, Monteverde M, Matin R, Purdie K, Mladkova N, Bergamaschi D et al (2012) NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. Br J Cancer 106(8):1446–1452Google Scholar
  27. 27.
    Wang R, Zhang Y, Lin X, Gao Y, Zhu Y (2017) Prognositic value of CD73-adenosinergic pathway in solid tumor: a meta-analysis and systematic review. Oncotarget 8(34):57327–57336Google Scholar
  28. 28.
    Monteiro I, Vigano S, Faouzi M, Treilleux I, Michielin O, Menetrier-Caux C, Caux C, Romero P, de Leval L (2018) CD73 expression and clinical significance in human metastatic melanoma. Oncotarget 9(42):26659–26669Google Scholar
  29. 29.
    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2(5):401–404Google Scholar
  30. 30.
    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E et al (2013) Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 6(269):pl1Google Scholar
  31. 31.
    La Rosa S, Adsay V, Albarello L, Asioli S, Casnedi S, Franzi F, Marando A, Notohara K, Sessa F, Vanoli A et al (2012) Clinicopathologic study of 62 acinar cell carcinomas of the pancreas: insights into the morphology and immunophenotype and search for prognostic markers. Am J Surg Pathol 36(12):1782–1795Google Scholar
  32. 32.
    Brierley JDGM, Wittekind C (2016) TNM classification of malignant tumours, 8th edn. Wiley, New yorkGoogle Scholar
  33. 33.
    Airas L (1998) CD73 and adhesion of B-cells to follicular dendritic cells. Leuk Lymphoma 29(1–2):37–47Google Scholar
  34. 34.
    Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F et al (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26(2):259–271Google Scholar
  35. 35.
    Allard D, Allard B, Gaudreau PO, Chrobak P, Stagg J (2016) CD73-adenosine: a next-generation target in immuno-oncology. Immunotherapy 8(2):145–163Google Scholar
  36. 36.
    Zimmermann H (1992) 5′-Nucleotidase: molecular structure and functional aspects. Biochem J 285(Pt 2):345–365Google Scholar
  37. 37.
    Monges GM, Mathoulin-Portier MP, Acres RB, Houvenaeghel GF, Giovannini MF, Seitz JF, Bardou VJ, Payan MJ, Olive D (1999) Differential MUC 1 expression in normal and neoplastic human pancreatic tissue. An immunohistochemical study of 60 samples. Am J Clin Pathol 112(5):635–640Google Scholar
  38. 38.
    Knudsen ES, Vail P, Balaji U, Ngo H, Botros IW, Makarov V, Riaz N, Balachandran V, Leach S, Thompson DM et al (2017) Stratification of pancreatic ductal adenocarcinoma: combinatorial genetic, stromal, and immunologic markers. Clin Cancer Res 23(15):4429–4440Google Scholar
  39. 39.
    Inarrairaegui M, Melero I, Sangro B (2018) Immunotherapy of hepatocellular carcinoma: facts and hopes. Clin Cancer Res 24(7):1518–1524Google Scholar
  40. 40.
    Gao HL, Liu L, Qi ZH, Xu HX, Wang WQ, Wu CT, Zhang SR, Xu JZ, Ni QX, Yu XJ (2018) The clinicopathological and prognostic significance of PD-L1 expression in pancreatic cancer: a meta-analysis. Hepatobiliary Pancreat Dis Int 17(2):95–100Google Scholar
  41. 41.
    Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C, Luciani A, Zafrani ES, Laurent A, Azoulay D et al (2016) Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology 64(6):2038–2046Google Scholar
  42. 42.
    Ohta A (2016) A metabolic immune checkpoint: adenosine in tumor microenvironment. Front Immunol 7:109Google Scholar
  43. 43.
    Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, Ohta A, Thiel M (2004) Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 22:657–682Google Scholar
  44. 44.
    Allard B, Pommey S, Smyth MJ, Stagg J (2013) Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res 19(20):5626–5635Google Scholar
  45. 45.
    Shirabe K, Motomura T, Muto J, Toshima T, Matono R, Mano Y, Takeishi K, Ijichi H, Harada N, Uchiyama H et al (2010) Tumor-infiltrating lymphocytes and hepatocellular carcinoma: pathology and clinical management. Int J Clin Oncol 15(6):552–558Google Scholar
  46. 46.
    Chang JH, Jiang Y, Pillarisetty VG (2016) Role of immune cells in pancreatic cancer from bench to clinical application: an updated review. Medicine (Baltim) 95(49):e5541Google Scholar
  47. 47.
    Leone RD, Emens LA (2018) Targeting adenosine for cancer immunotherapy. J Immunother Cancer 6(1):57Google Scholar
  48. 48.
    Haun RS, Quick CM, Siegel ER, Raju I, Mackintosh SG, Tackett AJ (2015) Bioorthogonal labeling cell-surface proteins expressed in pancreatic cancer cells to identify potential diagnostic/therapeutic biomarkers. Cancer Biol Ther 16(10):1557–1565Google Scholar
  49. 49.
    Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, Hansen KR, Thompson LF, Colgan SP (2002) Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Investig 110(7):993–1002Google Scholar
  50. 50.
    Kim Y, Lin Q, Glazer PM, Yun Z (2009) Hypoxic tumor microenvironment and cancer cell differentiation. Curr Mol Med 9(4):425–434Google Scholar
  51. 51.
    Zhang B (2010) CD73: a novel target for cancer immunotherapy. Cancer Res 70(16):6407–6411Google Scholar
  52. 52.
    Yu J, Liao X, Li L, Lv L, Zhi X, Yu J, Zhou P (2017) A preliminary study of the role of extracellular—5′-nucleotidase in breast cancer stem cells and epithelial-mesenchymal transition. In vitro Cell Dev Biol Anim 53(2):132–140Google Scholar
  53. 53.
    Valcourt U, Carthy J, Okita Y, Alcaraz L, Kato M, Thuault S, Bartholin L, Moustakas A (2016) Analysis of epithelial-mesenchymal transition induced by transforming growth factor beta. Methods Mol Biol (Clifton NJ) 1344:147–181Google Scholar
  54. 54.
    Zhang L, Huang G, Li X, Zhang Y, Jiang Y, Shen J, Liu J, Wang Q, Zhu J, Feng X et al (2013) Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor—1alpha in hepatocellular carcinoma. BMC Cancer 13:108Google Scholar
  55. 55.
    Yoshimura A, Muto G (2011) TGF-beta function in immune suppression. Curr Top Microbiol Immunol 350:127–147Google Scholar
  56. 56.
    Xiong L, Wen Y, Miao X, Yang Z (2014) NT5E and FcGBP as key regulators of TGF-1-induced epithelial-mesenchymal transition (EMT) are associated with tumor progression and survival of patients with gallbladder cancer. Cell Tissue Res 355(2):365–374Google Scholar
  57. 57.
    Maier HJ, Wirth T, Beug H (2010) Epithelial-mesenchymal transition in pancreatic carcinoma. Cancers 2(4):2058–2083Google Scholar
  58. 58.
    Reinhardt J, Landsberg J, Schmid-Burgk JL, Ramis BB, Bald T, Glodde N, Lopez-Ramos D, Young A, Ngiow SF, Nettersheim D et al (2017) MAPK signaling and inflammation link melanoma phenotype switching to induction of CD73 during immunotherapy. Cancer Res 77(17):4697–4709Google Scholar
  59. 59.
    Ono K, Shiozawa E, Ohike N, Fujii T, Shibata H, Kitajima T, Fujimasa K, Okamoto N, Kawaguchi Y, Nagumo T et al (2018) Immunohistochemical CD73 expression status in gastrointestinal neuroendocrine neoplasms: a retrospective study of 136 patients. Oncol Lett 15(2):2123–2130Google Scholar
  60. 60.
    Hackeng WM, Hruban RH, Offerhaus GJ, Brosens LA (2016) Surgical and molecular pathology of pancreatic neoplasms. Diagn Pathol 11(1):47Google Scholar
  61. 61.
    Lutz ER, Kinkead H, Jaffee EM, Zheng L (2014) Priming the pancreatic cancer tumor microenvironment for checkpoint-inhibitor immunotherapy. Oncoimmunology 3(11):e962401Google Scholar
  62. 62.
    Kasper HU, Drebber U, Stippel DL, Dienes HP, Gillessen A (2009) Liver tumor infiltrating lymphocytes: comparison of hepatocellular and cholangiolar carcinoma. World J Gastroenterol 15(40):5053–5057Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Service of Clinical Pathology, Institute of PathologyLausanne University HospitalLausanneSwitzerland
  2. 2.Innovation in Immuno-monitoring and Immunotherapy Platform (PI3)Léon Bérard Cancer CenterLyonFrance
  3. 3.Department of Visceral SurgeryLausanne University HospitalLausanneSwitzerland
  4. 4.Department of Oncology, Faculty of Biology and MedicineUniversity of LausanneLausanneSwitzerland

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