CD73 as a potential opportunity for cancer immunotherapy

Ghalamfarsa, Ghasem; Kazemi, Mohammad Hossein; Mohseni, Sahar Raoofi; Masjedi, Ali; Hojjat‐Farsangi, Mohammad; Azizi, Gholamreza; Yousefi, Mehdi; Jadidi‐Niaragh, Farhad

doi:10.1080/14728222.2019.1559829

Cited by 119 publications

(107 citation statements)

References 125 publications

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“…Since the enzymatic activity of CD73 and CD39 drives the production of immunosuppressive ADO, CD73 and CD39 have been identified as a novel immune checkpoint targets [17,39,40]. Both CD73 and CD39 can be also expressed on immune cells [41].…”

Section: Discussionmentioning

confidence: 99%

Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming

et al. 2020

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Glioblastoma (GBM) is the most aggressive malignant primary brain tumour in adulthood. Despite strong research efforts current treatment options have a limited impact on glioma stem-like cells (GSCs) which contribute to GBM formation, progression and chemoresistance. Invasive growth of GSCs is in part associated with epithelial–mesenchymal-like transition (EMT), a mechanism associated with CD73 in several cancers. Here, we show that CD73 regulates the EMT activator SNAIL1 and further investigate the role of enzymatic and non-enzymatic CD73 activity in GBM progression. Reduction of CD73 protein resulted in significant suppression of GSC viability, proliferation and clonogenicity, whereas CD73 enzymatic activity exhibited negative effects only on GSC invasion involving impaired downstream adenosine (ADO) signalling. Furthermore, application of phosphodiesterase inhibitor pentoxifylline, a potent immunomodulator, effectively inhibited ZEB1 and CD73 expression and significantly decreased viability, clonogenicity, and invasion of GSC in vitro cultures. Given the involvement of adenosine and A3 adenosine receptor in GSC invasion, we investigated the effect of the pharmacological inhibition of A3AR on GSC maintenance. Direct A3AR inhibition promoted apoptotic cell death and impaired the clonogenicity of GSC cultures. Taken together, our data indicate that CD73 is an exciting novel target in GBM therapy. Moreover, pharmacological interference, resulting in disturbed ADO signalling, provides new opportunities to innovate GBM therapy.

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Section: Discussionmentioning

confidence: 99%

Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming

et al. 2020

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“…As previously described, the ectonucleotidases CD39 and CD73 hydrolyze ATP or ADP into AMP and further yield adenosine in a highly coordinated enzymatic process [88,89]. CD39 and CD73 are expressed by cancer cells and different immune cell populations and are responsible for the regulation of the balance between proinflammatory ATP and immunosuppressive adenosine in the tumor microenvironment [48,49,90,91]. Li et al demonstrated that CD39 and CD73 were expressed on MDSCs in the peripheral blood of patients with NSCLC and that CD39 + CD73 + MDSCs had an immunosuppressive function.…”

Section: Mdscs Are Associated With Chemotherapy Resistancementioning

confidence: 99%

Myeloid-derived suppressor cells—new and exciting players in lung cancer

et al. 2020

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Lung cancer (LC) is the leading cause of cancer-related death worldwide due to its late diagnosis and poor outcomes. As has been found for other types of tumors, there is increasing evidence that myeloid-derived suppressor cells (MDSCs) play important roles in the promotion and progression of LC. Here, we briefly introduce the definition of MDSCs and their immunosuppressive functions. We next specifically discuss the multiple roles of MDSCs in the lung tumor microenvironment, including those in tumor growth and progression mediated by inhibiting antitumor immunity, and the associations of MDSCs with a poor prognosis and increased resistance to chemotherapy and immunotherapy. Finally, we also discuss preclinical and clinical treatment strategies targeting MDSCs, which may have the potential to enhance the efficacy of immunotherapy.

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“…Adenosine has multiple functions aimed at maintaining tissue homeostasis, and mediates its immunosuppressive effects mainly via A2A and A2B receptors ( 9 ). CD73 is upregulated in several types of cancer and increasing evidence suggested that CD73 plays a crucial role in the control of tumor progression ( 10 – 12 ). It was demonstrated that inhibition of CD73 activity or CD73 knockdown on tumor cells inhibited tumor growth by enhancing the antitumor T-cell response ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

CD73 promotes colitis‑associated tumorigenesis in mice

Liu

Lan

et al. 2020

Oncol Lett

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Patients with inflammatory bowel disease (IBD) are at a higher risk of developing colitis-associated colorectal cancer. The aim of the present study was to investigate the role of CD73 in IBD-associated tumorigenesis. A mouse model of colitis-associated tumorigenesis (CAT) induced by azoxymethane and dextran sulfate sodium was successfully constructed. Model mice were injected with CD73 inhibitor or adenosine receptor agonist. Colon length, body weight loss and tumor formation were assessed macroscopically. Inflammatory cytokine measurement and RNA sequencing on colon tissues were performed. Inhibition of CD73 by adenosine 5'-(α,β-methylene) diphosphate (APCP) suppressed the severity of CAT with attenuated weight loss, longer colons, lower tumor number and smaller tumor size compared with the model group. Activation of adenosine receptors using 1-(6-amino-9H-purin-9-yl)-1-deoxy-N-ethyl-β-D-ribofuranur onamide (NECA) exacerbated CAT. Histological assessment indicated that inhibition of CD73 reduced, while activation of adenosine receptors exacerbated, the histological damage of the colon. Increased expression of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-6) in colonic tissue was detected in the NECA group. According to RNA sequencing results, potential oncogenes such as arachidonate 15-lipoxygenase (ALOX15), Bcl-2-like protein 15 (Bcl2l15) and N-acetylaspartate synthetase (Nat8l) were downregulated in the APCP group and upregulated in the NECA group compared with the model group. Therefore, inhibition of CD73 attenuated IBD-associated tumorigenesis, while activation of adenosine receptors exacerbated tumorigenesis in a C57BL/6J mouse model. This effect may be associated with the expression of pro-inflammatory cytokines and the regulation of ALOX15, Bcl2l15 and Nat8l.

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CD73 as a potential opportunity for cancer immunotherapy

Cited by 119 publications

References 125 publications

Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming

Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming

Myeloid-derived suppressor cells—new and exciting players in lung cancer

CD73 promotes colitis‑associated tumorigenesis in mice

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