Combination
therapies for
melanoma that target immune-regulatory networks are entering clinical practice, and more are under investigation in preclinical or clinical studies.
Adenosine plays a key role in regulating
melanoma progression. We investigated the effectiveness of
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody (mAb) in combination with either modulators of
adenosine receptors (AR) activation or an inhibitor of
adenosine production in a murine model of
melanoma. We found that treatment with
APCP, selective inhibitor of the
adenosine-generating
nucleotidase CD73, enhanced the activity of anti-CTLA4 mAb, by improving
tumor immune response. Blockade of the
adenosine A2a receptor (A2aR), which plays a critical role in the regulation of T-cell functions, significantly reduced
melanoma growth. Most importantly, combination
therapy including an A2aR antagonist with anti-CTLA4 mAb markedly inhibited
tumor growth and enhanced anti-
tumor immune responses. Targeting A3R and CTLA4 was not as effective in limiting
melanoma growth as targeting A2aR. These data suggest that the efficacy of anti-CTLA4
melanoma therapy may be improved by targeting multiple mechanisms of immune suppression within
tumor tissue, including CD73 or A2a receptor.