CD39 and tumor
CD39 is expressed in tumor cells and tumor-infiltrating immune cells and affects tumor development in various interrelated ways. CD39 is up-regulated in a variety of human cancers, such as leukemia and head, neck, colorectal, liver, and gastric cancers, and the expression level of CD39 is often related to the stage and severity of a disease[172-178]. CD39 is highly expressed on tumor-infiltrating immune cells, particularly effector T-cells and Tregs. CD39 has been shown to be highly expressed in tumor-infiltrating CD8+ T-cells in a variety of human tumors, including renal cell carcinoma, gastric cancer [39], lung cancer, colorectal cancer, breast cancer [40] and head and neck cancer [41]. Tumor-infiltrating CD39highCD8+ T-cells increase with tumor growth, and exhibit features of exhaustion, including decreased TNF, IL-2, and IFN-γ production as well as increased expression of many inhibitory/checkpoint receptors, such as programmed cell death 1, T cell immunoglobulin and mucin-do-main-containing molecule 3, Lymphocyte-activation gene 3, T cell immunoglobulin and ITIM domain, and 2B4 [40]. Tregs mediate immunosuppression through several mechanisms, including CD39-dependent production of ADO. Transcriptional profiling of Tregs revealed a substantial number of candidate genes with the potential to mediate suppression, including the highly expressed CD39 [36]. CD39 was found expressed in CD8+ Tregs, and CD39 expression correlated with suppression activity mediated by CD8+Tregs [179]. Hu et al. identified a novel CD39+ γδTreg in human colorectal cancer patients[35]. Furthermore, the CD39+γδTregs are the predominant regulatory T-cells observed in colorectal cancer patients, with a more potent immunosuppressive activity than CD4+ or CD8+ Tregs, and acting through the ADO-mediated pathway [35]. Tumor-infiltrating CD39⁺ Tregs accumulate in colon tumors and exhibit high expression of surface molecules related to immunosuppression, such as inducible co-stimulator, programmed cell death protein ligand 1, and cytotoxic T lymphocyte associated antigen 4. CD39⁺ Tregs also show potent suppressive capacity on proliferation and IFN-γ secretion by conventional T-cells [37]. In patients with colon cancer, circulating Tregs express high levels of CD39, which contributes to the reduced transendothelial migration of effector T-cells into tumors [180]. Lower baseline levels of circulating Tregs (CD4+CD25highCD39+) in melanoma patients were associated with better relapse-free survival[181]. There are few studies on the role of CD39 in anti-tumor immunity mediated by NK cells. Zhang et al. found that CD39 was expressed in tumor-infiltrating NK cells. Furthermore, POM-1 suppressed experimental and spontaneous metastases in four tumor models, and its anti-metastatic activity was completely abrogated in NK-cell-depleted mice [72]. The proportion of NK cells significantly decreased, but CD39 was obviously up-regulated in NK cells from cancerous tissues compared to paired peripheral blood in esophageal squamous cell carcinoma patients. Furthermore, tumor-infiltrating CD39+ NK cells exhibited a phenotype of functional impairment and were correlated with poor prognosis [182]. Myeloid-derived suppressor cells (MDSCs) have been recognized as one of major contributors to tumor-induced immunosuppression [183]. MDSCs in peripheral blood and tumor tissues from patients with non-small cell lung cancer were shown to express CD39. Tumor TGF-β stimulated CD39 and CD73 expression in MDSCs, thereby inhibited T cell and NK cell activity, and protected tumor cells from the cytotoxic effect of chemotherapy through ectonucleotidase activity [184]. Compared to other myeloid cells present in the blood of patients with colorectal cancer, gMDSCs that expressed high levels of PD-L1, CD39, and CD73 exerted a robust immunosuppressive activity,[185]. Metformin treatment blocks the suppressive function of MDSCs in patients with ovarian cancer by down-regulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets [186]. In addition, the growth of multiple syngeneic tumors is reduced in global CD39 gene-targeted mice [95, 187, 188]. Similarly, CD39-deficient mice are resistant to the formation of metastasis in models of disseminated disease or spontaneous metastasis[72, 189]. In a dissemination liver metastasis model, MC-26 cell line-derived hepatic metastases grew significantly faster in CD39 over-expressing transgenic mice when compared to those in CD39-deficient mice [190]. Additionally, pharmacological blockade of CD39 activity with an antagonistic antibody or the inhibitor POM-1 was shown to significantly limit tumor growth and improve anti-tumor immunity [187, 189, 191, 192].