CD39 and NK cells
It has been reported that the expression of CD39 is very low in resting human NK cells [56]. In murine NK cells, CD39 is the dominant ectonucleotidase and thereby plays a predominant role in the regulation of pericellular nucleotide concentration levels. While murine NK cells do not express CD73 and cannot efficiently generate ADO, they primarily mediate ATP and ADP hydrolysis into AMP[67]. However, the human NK cells were shown to produce ADO via a CD38-mediated pathway [68].
CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, and limiting tissue damage mediated by these innate immune cells during IRI [67]. In addition, CD39 deletion has been shown to have a protective effect in the context of concanavalin A hepatitis induced by NKT cells [69]. Additional protective effects of CD39 deletion have been demonstrated in the context of invariant NKT cell-mediated hyperoxic acute lung injury[70]. After trauma, the subsets of NK cells changed significantly, and the expression of surface CD39 increased in those NK cells. The observed post-injury increase in CD39 expression levels in NK cells provides an explanation for the susceptibility to infection of those patients, and it might represent a potential prognostic marker or drug target [71].
In a tumor setting, the expression of CD39 and the consequential ATP hydrolysis and ADO generation compromise anti-tumor immune responses, including those that may be mediated by NK cells. Zhang et al. showed that both CD39 and CD73 are up-regulated in lung tumor-infiltrating NK cells [72]. Furthermore, the same study demonstrated that NTPDase inhibitor sodium polyoxotungstate (POM-1) enhanced NK cell-mediated metastatic control and synergized with combined Braf and MEK inhibition, recombinant IL-2, or anti-PD-1 and anti-CTLA-4 checkpoint blockade. Moreover, Yan et al. showed that the anti-metastatic activity of anti-CD39 was NK cell- and IFN-γ-dependent and that the quantity of IFN-γ produced in lung-infiltrating NK cells was enhanced following tumor challenge and anti-CD39 therapy[73].