CD73 expression in normal and pathological human hepatobiliopancreatic tissues

Sciarra, Amedeo; Monteiro, Inês; Ménétrier‐Caux, Christine; Caux, Christophe; Gilbert, Benoît; Halkic, Nermin; Rosa, Stefano La; Romero, Pedro; Sempoux, Christine; Leval, Laurence de

doi:10.1007/s00262-018-2290-1

Cited by 28 publications

(31 citation statements)

References 62 publications

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“…NT5E-2 expression was not assessed in these studies, which is a limitation. In line with CD73s expression, Sciarra et al (172) especially noted significant cytoplasmic CD73 expression in tumors, particularly with invasive tumors (172) ( Table 2).…”

Section: Liver Cancermentioning

confidence: 74%

“…Well-and moderately-differentiated PDAC cells express mixed membrane and cytoplasmic CD73 staining. CD73 staining intensity is low to moderate in these tumors (172). In contrast, poorly-differentiated PDAC cells have aberrant CD73 staining, including very strong cytoplasmic CD73 expression (172).…”

Section: Pancreatic Cancermentioning

confidence: 93%

“…CD73 staining intensity is low to moderate in these tumors (172). In contrast, poorly-differentiated PDAC cells have aberrant CD73 staining, including very strong cytoplasmic CD73 expression (172). The increase of cytoplasmic CD73 expression in PDAC is unclear.…”

Section: Pancreatic Cancermentioning

confidence: 94%

“…CD73 is upregulated in PDAC compared to normal pancreatic tissue and correlates with increased tumor size, advanced stage, lymph node involvement, metastasis, and poor prognosis (77,80,172). While PDAC tumors are 100% positive for CD73 expression (172), interesting staining patterns for CD73 are seen. Well-and moderately-differentiated PDAC cells express mixed membrane and cytoplasmic CD73 staining.…”

Section: Pancreatic Cancermentioning

confidence: 99%

“…Studies assessing NT5E-2 (CD73s) expression may help to better understand CD73 in PDAC. CD73 expression in acinar cell carcinomas (ACC) is rare (172). ACC comprises 1-2% of pancreatic tumors and does not carry typical genomic alterations seen in PDAC, including KRAS and TP53 mutations (205), which is suggestive that CD73 expression in PDAC may be linked to KRAS and/or TP53 mutations.…”

Section: Pancreatic Cancermentioning

confidence: 99%

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CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

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Section: Liver Cancermentioning

confidence: 74%

Section: Pancreatic Cancermentioning

confidence: 93%

Section: Pancreatic Cancermentioning

confidence: 94%

Section: Pancreatic Cancermentioning

confidence: 99%

Section: Pancreatic Cancermentioning

confidence: 99%

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CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma

Alcedo

Guerrero

Basrur³

et al. 2019

Hepatol Commun

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CD73, a cell‐surface N‐linked glycoprotein that produces extracellular adenosine, is a novel target for cancer immunotherapy. Although anti‐CD73 antibodies have entered clinical development, CD73 has both protumor and antitumor functions, depending on the target cell and tumor type. The aim of this study was to characterize CD73 regulation in human hepatocellular carcinoma (HCC). We examined CD73 expression, localization, and activity using molecular, biochemical, and cellular analyses on primary HCC surgical specimens, coupled with mechanistic studies in HCC cells. We analyzed CD73 glycan signatures and global alterations in transcripts encoding other N‐linked glycoproteins by using mass spectrometry glycomics and RNA sequencing (RNAseq), respectively. CD73 was expressed on tumor hepatocytes where it exhibited abnormal N‐linked glycosylation, independent of HCC etiology, tumor stage, or fibrosis presence. Aberrant glycosylation of tumor‐associated CD73 resulted in a 3‐fold decrease in 5′‐nucleotidase activity (P < 0.0001). Biochemically, tumor‐associated CD73 was deficient in hybrid and complex glycans specifically on residues N311 and N333 located in the C‐terminal catalytic domain. Blocking N311/N333 glycosylation by site‐directed mutagenesis produced CD73 with significantly decreased 5′‐nucleotidase activity in vitro, similar to the primary tumors. Glycosylation‐deficient CD73 partially colocalized with the Golgi structural protein GM130, which was strongly induced in HCC tumors. RNAseq analysis further revealed that N‐linked glycoprotein‐encoding genes represented the largest category of differentially expressed genes between HCC tumor and adjacent tissue. Conclusion: We provide the first detailed characterization of CD73 glycosylation in normal and tumor tissue, revealing a novel mechanism that leads to the functional suppression of CD73 in human HCC tumor cells. The present findings have translational implications for therapeutic candidate antibodies targeting cell‐surface CD73 in solid tumors and small‐molecule adenosine receptor agonists that are in clinical development for HCC.

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The role of the CD39–CD73–adenosine pathway in liver disease

Wang

Gao

Zhou

et al. 2020

Journal Cellular Physiology

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Extracellular adenosine triphosphate (ATP) is a danger signal released by dying and damaged cells, and it functions as an immunostimulatory signal that promotes inflammation. The ectonucleotidases CD39/ectonucleoside triphosphate diphosphohydrolase-1 and CD73/ecto-5′-nucleotidase are cell-surface enzymes that breakdown extracellular ATP into adenosine. This drives a shift from an ATP-driven proinflammatory environment to an anti-inflammatory milieu induced by adenosine. The CD39-CD73-adenosine pathway changes dynamically with the pathophysiological context in which it is embedded. Accumulating evidence suggests that CD39 and CD73 play important roles in liver disease as critical components of the extracellular adenosinergic pathway. Recent studies have shown that the modification of the CD39-CD73-adenosine pathway alters the liver's response to injury. Moreover, adenosine exerts different effects on the pathophysiology of the liver through different receptors. In this review, we aim to describe the role of the CD39-CD73-adenosine pathway and adenosine receptors in liver disease, highlighting potential therapeutic targets in this pathway, which will facilitate the development of therapeutic strategies for the treatment of liver disease.

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CD73 expression in normal and pathological human hepatobiliopancreatic tissues

Cited by 28 publications

References 62 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Tumor‐Selective Altered Glycosylation and Functional Attenuation of CD73 in Human Hepatocellular Carcinoma

The role of the CD39–CD73–adenosine pathway in liver disease

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