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].