The distinct role of CD73 in the progression of pancreatic cancer

Zhou, Linhua; Jia, Shengnan; Chen, Yan; Wang, Weiming; Wu, Zhengrong; Yu, Weihua; Zhang, Mingjie; Ding, Guoping; Cao, Liping

doi:10.1007/s00109-018-01742-0

Cited by 56 publications

(64 citation statements)

References 40 publications

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“…These mice also benefit from increased chemotherapy sensitivity (36,71) and reduced angiogenesis (71,72). In line with these studies, many human tumors overexpress CD73 and associates with poor prognosis (36,(73)(74)(75)(76)(77)(78). CD73 is also linked to drug resistance, epithelial-to-mesenchymal transition (EMT), and cancer cell proliferation and stemness (76,(79)(80)(81)(82)(83)(84).…”

Section: Cd73 and Adenosine Receptor Activity Promotes Immunosuppressionmentioning

confidence: 77%

“…Many immunohistochemistry data for high CD73 expressing tumors, including gastric and pancreatic cancer, show significant cytoplasmic staining of CD73 (75,77). Current commercial antibodies are not marketed to distinguish between CD73 and CD73s.…”

Section: Liver Cancermentioning

confidence: 99%

“…Studies of CD73 in human PDAC tissue have only recently emerged ( Table 2). 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.…”

Section: Pancreatic Cancermentioning

confidence: 99%

“…CD73 also shows to promote drug resistance and tumor growth in PDAC cells. For instance, high CD73 expression and low miR-30a-5p expression in PDAC cells result in chemotherapy (e.g., gemcitabine) resistance (77), and CD73 knockdown inactivates AKT and extracellular signal-regulated kinase (ERK) signaling and slows cancer cell growth (77). In contrast, studies show extracellular adenosine treatment in combination with AKT inhibitor, GSK690693, reduces PDAC growth and induces tumor cell apoptosis and senescence in patient-derived xenografts (PDX).…”

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: Cd73 and Adenosine Receptor Activity Promotes Immunosuppressionmentioning

confidence: 77%

Section: Liver Cancermentioning

confidence: 99%

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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“…In PDAC, apoptotic Treg in the hypoxic TME was shown to express a high amount of the CD73 enzyme that converts adenosine triphosphate to adenosine, contributing to the inhibition of cytokine expression of Teff ( Figure 1 ). In a xenograft nude mouse model, knockdown of CD73 resulted in slow tumor growth and increased sensitivity to gemcitabine [ 87 ]. The authors also showed that human PDAC tissues express attenuated levels of miR-30a-5p, which regulates CD73 protein level, suggesting that tumor growth can be inhibited by elevating miR-30a-5p levels by gene therapy to relieve immunosuppressive conditions and improve gemcitabine sensitivity [ 87 ].…”

Section: Influence Of the Pancreatic Tumor Microenvironment On Thementioning

confidence: 99%

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Saka

Gökalp

Piyade

et al. 2020

Cancers

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T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.

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Second‐Generation CD73 Inhibitors Based on a 4,6‐Biaryl‐2‐thiopyridine Scaffold

et al. 2023

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Various series of 4,6‐biaryl‐2‐thiopyridine derivatives were synthesized and evaluated as potential ecto‐5′‐nucleotidase (CD73) inhibitors. Two synthetic routes were explored and the coupling of 4,6‐disubstituted 3‐cyano‐2‐chloro‐pyridines with selected thiols allowed us to explore the structural diversity. Somehow divergent results were obtained in biological assays on CD73 inhibition using either the purified recombinant protein or cell‐based assays, highlighting the difficulty to target protein‐protein interface on proteins existing as soluble and membrane‐bound forms. Among the 18 new derivatives obtained, three derivatives incorporating morpholino substituents on the 4,6‐biaryl‐2‐thiopyridine core were shown to be able to reverse the adenosine‐mediated immune suppression on human T cells. The higher blockade efficiency was observed for 2‐((3‐cyano‐4,6‐bis(4‐morpholinophenyl)pyridin‐2‐yl)thio)‐N‐(isoxazol‐3‐yl)acetamide (with total reversion at 100 μM) and methyl 2‐((3‐cyano‐4,6‐bis(4‐morpholinophenyl)pyridin‐2‐yl)thio)acetate (with partial reversion at 10 μM). Thus, this series of compounds illustrates a new chemotype of CD73 allosteric inhibitors.

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The distinct role of CD73 in the progression of pancreatic cancer

Cited by 56 publications

References 40 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Mechanisms of T-Cell Exhaustion in Pancreatic Cancer

Second‐Generation CD73 Inhibitors Based on a 4,6‐Biaryl‐2‐thiopyridine Scaffold

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