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].