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Am J Cancer Res. 2014 Mar 1;4(2):172-81. eCollection 2014.

Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model.

Author information

1
Department of Pharmacy, University of Salerno Italy.
2
Cancer Institute and Departments of Medicine and Pharmacology, University of Mississippi Medical Center Jackson, MS 39216, USA.
3
National Cancer Institute "Pascale", Pharmacy Unit Naples, Italy.

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.

KEYWORDS:

CD73; CTLA4; adenosine receptor; immunotherapy; melanoma

PMID:
24660106
PMCID:
PMC3960454

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