Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses

Paul A Beavis; Nicole Milenkovski; Melissa A Henderson; Liza B John; Bertrand Allard; Sherene Loi; Michael H Kershaw; John Stagg; Phillip K Darcy

Journal article

Adenosine Receptor 2A Blockade Increases the Efficacy of Anti-PD-1 through Enhanced Antitumor T-cell Responses

Paul A Beavis, Nicole Milenkovski, Melissa A Henderson, Liza B John, Bertrand Allard, Sherene Loi, Michael H Kershaw, John Stagg, Phillip K Darcy

CANCER IMMUNOLOGY RESEARCH | AMER ASSOC CANCER RESEARCH | Published : 2015

DOI: 10.1158/2326-6066.CIR-14-0211

Abstract

Immunotherapy is rapidly emerging as a cancer treatment with high potential. Recent clinical trials with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies (mAbs) suggest that targeting multiple immunosuppressive pathways may significantly improve patient survival. The generation of adenosine by CD73 also suppresses antitumor immune responses through the activation of A2A receptors on T cells and natural killer (NK) cells. We sought to determine whether blockade of A2A receptors could enhance the efficacy of anti-PD-1 mAb. The expression of CD73 by tumor cells limited the efficacy of anti-PD-1 mAb in two tumor models, and this was alleviated with concomitant treatment with an A2A adenosine receptor ..

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University of Melbourne Researchers

Phillip Darcy Author The Sir Peter Maccallum Department of Oncology

Sherene Loi Author The Sir Peter Maccallum Department of Oncology

Paul Beavis Author The Sir Peter Maccallum Department of Oncology

Michael Kershaw Author The Sir Peter Maccallum Department of Oncology

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Grants

Awarded by National Health and Medical Research Council (NHMRC)

Awarded by National Breast Cancer Fellowship

Awarded by NHMRC

Awarded by National Breast Cancer Foundation

Awarded by National Health and Medical Research Council of Australia

Funding Acknowledgements

This work was funded by a Project Grant from the National Health and Medical Research Council (NHMRC; 1062580). P.A. Beavis was supported by a National Breast Cancer Fellowship (PF-14-008). P.K. Darcy and M.H. Kershaw were supported by NHMRC Senior Research Fellowships (1041828 and 1058388, respectively). J. Stagg was supported by an Operating Grant (Remodeling of the tumor microenvironment by CD73: a therapeutic target) from the Canadian Institutes of Health Research.