Inhibition of CD39 Enzymatic Function at the Surface of Tumor Cells Alleviates Their Immunosuppressive Activity

Abstract

The ectonucleotidases CD39 and CD73 hydrolyze extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to generate adenosine, which binds to adenosine receptors and inhibits T-cell and natural killer (NK)-cell responses, thereby suppressing the immune system. The generation of adenosine via the CD39/CD73 pathway is recognized as a major mechanism of regulatory T cell (Treg) inhibited the proliferation of CD4 and CD8 T cells and the generation of cytotoxic effector CD8 T cells (CTL) in a CD39-and adenosine-dependent manner. Treatment with a CD39 inhibitor or blocking antibody alleviated the tumor-induced inhibition of CD4 and CD8 T-cell proliferation and increased CTL-and NK cell-mediated cytotoxicity. In conclusion, interfering with the CD39-adenosine pathway may represent a novel immunotherapeutic strategy for inhibiting tumor cell-mediated immunosuppression.

CD39: A complementary target to immune checkpoints to counteract tumor-mediated immunosuppression

“…By measuring either extracellular ATP degradation or the release of free phosphate in cell culture supernatants, we demonstrated that all CD39-expressing cells display strong ATPase activity that is counteracted by the chemical CD39 inhibitors ARL 67156 and POM-1. 7 As previously described for ovarian tumor cells, 6 we found that some cancer cell lines also express CD73, suggesting that tumor cells co-expressing CD39 and CD73 may exert potent immunosuppressive actions via adenosine. Supporting this hypothesis, we demonstrated that the degradation of ATP into AMP and adenosine by the SK-MEL-5 melanoma cell line is associated with the suppression of CD4 C and CD8 C T-cell proliferation as well as the generation of cytotoxic effector CD8 C T cells.…”

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…31,36 CD39 belongs to the arsenal of regulatory T cells and ovarian cancer cells to generate an immunosuppressive environment. 43,46,59 Here, we describe that ovarian tumor-infiltrating macrophages are also active players of this process. Newly recruited monocytes in the tumor are in contact with ATPderived nucleotides which may participate to the acquisition of an IL-10 high IL-12 low immunosuppressive phenotype.…”

“…The field of cancer immunology has recently been fed with studies on the roles of the ectonucleotidases CD39 and CD73 on the biology of tumor-associated immune cells, showing that CD39 and/or adenosine receptors are major negative regulators of T cells, myeloid cells and cancer cells that could be targeted within the tumor microenvironment. 20,21,43 To support our choice to target CD39, it has been shown that CD73 (an ectonucleotidase hydrolyzing AMP into Adenosine) may be dispensable for M2-type macrophage polarization. 61 Numerous studies have underlined the role of IL-27 in the generation of an immunoregulatory microenvironment in physiological and pathological settings.…”

“…43,59 However, this effect might depend on the target cells and on the microenvironment. 66 IL-27 polymorphisms affecting IL-27 have been associated to an increased susceptibility to ovarian cancer.…”

“…In tumors, all these partners are present: (i) ATP is mainly released by dying cells and infiltrated immune cells, 12,13 (ii) CD39 and CD73 are expressed by numerous primary tumor cells 43,44 and by some infiltrating immunosuppressive cells [45][46][47][48] and (iii) adenosine receptor 2A is expressed by immune-infiltrating cells. 41 Furthermore, an accumulation of extracellular adenosine in tumor microenvironment and the subsequent purinergic signaling are involved in the regulation of immune cell functions.…”