Overexpression of CD73 in pancreatic ductal adenocarcinoma is associated with immunosuppressive tumor microenvironment and poor survival

Zhao, Jun; Soto, Luisa M. Solis; Wang, Hua; Katz, Matthew H.; Prakash, Laura R.; Kim, Michael; Tzeng, Ching‐Wei D.; Lee, Jeffrey E.; Wolff, Robert A.; Huang, Yanqing; Wistuba, Ignacio I.; Maitra, Anirban

doi:10.1016/j.pan.2021.03.018

Cited by 22 publications

(25 citation statements)

References 42 publications

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“…Analyses of pancreatic juice have identified soluble CD73 and implicate pancreatic ducts express CD73 and CD39 and are critical regulators of adenosine and purinergic signaling in pancreatic homeostasis (56). Studies relying on immunohistochemistry have reported normal pancreas does not stain positive for CD73 indicating in physiologic conditions, CD73 levels are low in exocrine pancreatic cells (57)(58)(59). In contrast, in human PDAC specimens, CD73 is highly expressed in a subset of patients and divergent patterns of immunolabeling have been reported (57,59,60).…”

Section: Discussionmentioning

confidence: 99%

“…Studies relying on immunohistochemistry have reported normal pancreas does not stain positive for CD73 indicating in physiologic conditions, CD73 levels are low in exocrine pancreatic cells (57)(58)(59). In contrast, in human PDAC specimens, CD73 is highly expressed in a subset of patients and divergent patterns of immunolabeling have been reported (57,59,60). Immunolabeling has shown in some patients, CD73 levels are high in malignant epithelial cells with limited staining in adjacent stroma.…”

Section: Discussionmentioning

confidence: 99%

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Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine

Singh

Faraoni

Dai

et al. 2021

Preprint

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The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding initial triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing novel targets for effective prevention and therapy. Here, we interrogate the differential molecular mechanisms dependent on cell of origin and pathology subtype that determine immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell of origin dependent-epithelial gene signatures revealed that Nt5e/CD73, a cell surface enzyme that is the pacemaker for extracellular adenosine generation, is one of the top 10% of genes over-expressed in murine tumors arising from ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by Imaging Mass Cytometry and High-Performance Liquid Chromatography. Our data indicate that ductal activation of oncogenic mutant Kras results in loss of PTEN and elevated AKT signaling which ultimately releases CD73 suppression. Delivery of CD73 small molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. Analysis in human PDAC subtypes indicates that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC Squamous and Basal Subtypes, considered to have the highest immunosuppression and worst prognosis. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment which is dependent on ductal cell of origin, linking biology with pathological subtype classification, critical components to personalized approaches for PDAC prevention and immunotherapeutic intervention.Abstract Figure

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine

Singh

Faraoni

Dai

et al. 2021

Preprint

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“…In addition to P1 receptors, CD73 is elevated in pancreatic cancer ( Chen et al, 2020 ; Zhao et al, 2021 ). In pancreatic cancer, adenosine generation mediated by the concerted activity of CD39 and CD73 is correlated with lower infiltration of CD8 + T cells and γδ + T cells, as well as stellate cell proliferation and collagen production ( Künzli et al, 2008 ; Chen et al, 2020 ; Shevchenko et al, 2020 ).…”

Section: Ductal Adenocarcinoma Of the Pancreasmentioning

confidence: 99%

Section: Ductal Adenocarcinoma Of the Pancreasmentioning

confidence: 99%

“…High expression of CD73 has been described in tumor cells in two independent cohorts of PDAC patients ( Chen et al, 2020 ; Zhao et al, 2021 ). Elevated CD73 is associated with a decrease in CD4 + , CD8 + , and CD21 + tumor-infiltrating lymphocytes and is associated with aggressive clinical behavior ( Zhao et al, 2021 ). Histologic evaluation of CD73 in pancreatic and PDAC tissues has shown CD73 is expressed in pancreatic ducts and in PDAC tissue, but not acinar cell carcinoma ( Sciarra et al, 2019 ).…”

Section: Ductal Adenocarcinoma Of the Pancreasmentioning

confidence: 99%

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Purinergic and Adenosinergic Signaling in Pancreatobiliary Diseases

Faraoni

Robson

et al. 2022

Front. Physiol.

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Adenosine 5'-triphosphate (ATP), other nucleotides, and the nucleoside analogue, adenosine, all have the capacity to modulate cellular signaling pathways. The cellular processes linked to extracellular purinergic signaling are crucial in the initiation, evolution, and resolution of inflammation. Injured or dying cells in the pancreatobiliary tract secrete or release ATP, which results in sustained purinergic signaling mediated through ATP type-2 purinergic receptors (P2R). This process can result in chronic inflammation, fibrosis, and tumor development. In contrast, signaling via the extracellular nucleoside derivative adenosine via type-1 purinergic receptors (P1R) is largely anti-inflammatory, promoting healing. Failure to resolve inflammation, as in the context of primary sclerosing cholangitis or chronic pancreatitis, is a risk factor for parenchymal and end-organ scarring with the associated risk of pancreatobiliary malignancies. Emerging immunotherapeutic strategies suggest that targeting purinergic and adenosinergic signaling can impact the growth and invasive properties of cancer cells, potentiate anti-tumor immunity, and also block angiogenesis. In this review, we dissect out implications of disordered purinergic responses in scar formation, end-organ injury, and in tumor development. We conclude by addressing promising opportunities for modulation of purinergic/adenosinergic signaling in the prevention and treatment of pancreatobiliary diseases, inclusive of cancer.

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CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism

Liu

Yuan

et al. 2022

Advanced Science

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CD73, a cell surface-bound nucleotidase, facilitates extracellular adenosine formation by hydrolyzing 5′-AMP to adenosine. Several studies have shown that CD73 plays an essential role in immune escape, cell proliferation and tumor angiogenesis, making it an attractive target for cancer therapies. However, there are limited clinical benefits associated with the mainstream enzymatic inhibitors of CD73, suggesting that the mechanism underlying the role of CD73 in tumor progression is more complex than anticipated, and further investigation is necessary. In this study, CD73 is found to overexpress in the cytoplasm of pancreatic ductal adenocarcinoma (PDAC) cells and promotes metastasis in a nucleotidase-independent manner, which cannot be restrained by the CD73 monoclonal antibodies or small-molecule enzymatic inhibitors. Furthermore, CD73 promotes the metastasis of PDAC by binding to the E3 ligase TRIM21, competing with the Snail for its binding site. Additionally, a CD73 transcriptional inhibitor, diclofenac, a non-steroidal anti-inflammatory drug, is more effective than the CD73 blocking antibody for the treatment of PDAC metastasis. Diclofenac also enhances the therapeutic efficacy of gemcitabine in the spontaneous KPC (LSL-Kras G12D/+ , LSL-Trp53 R172H/+ , and Pdx-1-Cre) pancreatic cancer model. Therefore, diclofenac may be an effective anti-CD73 therapy, when used alone or in combination with gemcitabine-based chemotherapy regimen, for metastatic PDAC.

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Overexpression of CD73 in pancreatic ductal adenocarcinoma is associated with immunosuppressive tumor microenvironment and poor survival

Cited by 22 publications

References 42 publications

Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine

Pancreatic cancer ductal cell of origin drives CD73-dependent generation of immunosuppressive adenosine

Purinergic and Adenosinergic Signaling in Pancreatobiliary Diseases

CD73, a Promising Therapeutic Target of Diclofenac, Promotes Metastasis of Pancreatic Cancer through a Nucleotidase Independent Mechanism

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