title: Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model.
abstract: 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.
authors.affiliation: Department of Pharmacy, University of Salerno Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Iannone
authors.affiliation: Cancer Institute and Departments of Medicine and Pharmacology, University of Mississippi Medical Center Jackson, MS 39216, USA.
authors.forename: Lucio
authors.initials: L
authors.lastname: Miele
authors.affiliation: National Cancer Institute "Pascale", Pharmacy Unit Naples, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Maiolino
authors.affiliation: Department of Pharmacy, University of Salerno Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Department of Pharmacy, University of Salerno Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Morello
keywords: CD73; CTLA4; adenosine receptor; immunotherapy; melanoma