Production of adenosine by ectonucleotidases: a key factor in tumor immunoescape

Abstract

It is now well known that tumor immunosurveillance contributes to the control of cancer growth. Many mechanisms can be used by cancer cells to avoid the antitumor immune response. One such mechanism relies on the capacity of cancer cells or more generally of the tumor microenvironment to generate adenosine, a major molecule involved in antitumor T cell response suppression. Adenosine is generated by the dephosphorylation of extracellular ATP released by dying tumor cells. The conversion of ATP into adenosine is mediated by ectonucleotidase molecules, namely, CD73 and CD39. These molecules are frequently expressed in the tumor bed by a wide range of cells including tumor cells, regulatory T cells, Th17 cells, myeloid cells, and stromal cells. Recent evidence suggests that targeting adenosine by inhibiting ectonucleotidases may restore the resident antitumor immune response or enhance the efficacy of antitumor therapies. This paper will underline the impact of adenosine and ectonucleotidases on the antitumor response.

Figure 1

Effects of adenosine produced by CD39+/CD73+ cells on target cells. Cancer cells, Tregs, Th17, and MDSCs could produce adenosine through degradation of ATP/ADP by CD39 and CD73. Then adenosine binds on target cells, such as immune cells, cancer cells, or endothelial cells and modifies their activity.

Figure 2

Hypoxia mediated expression of ectonucleotidases and adenosine receptors. HIF is induced under hypoxic conditions in cancer cells and directly increases the expression of (1) ectonucleotidases CD39 and CD73, which generate adenosine from ATP/ADP, (2) adenosine receptors that could, after binding of adenosine, activate HIF, and (3) angiogenic molecules VEGF and IL-8. These (again with β-FGF) also produced by endothelial cells (through binding of adenosine on specific receptors) could induce proliferation of these cells.