Altered purinergic signaling in CD73-deficient mice inhibits tumor progression

Authors

  • Gennady G. Yegutkin,

    1. MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland
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    • These authors contributed equally to this work.

  • Fumiko Marttila-Ichihara,

    1. MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland
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    • These authors contributed equally to this work.

  • Marika Karikoski,

    1. MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland
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    • These authors contributed equally to this work.

  • Jussi Niemelä,

    1. MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland
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    • These authors contributed equally to this work.

  • Juha P. Laurila,

    1. MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland
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  • Kati Elima,

    1. MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland
    2. Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland
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  • Sirpa Jalkanen,

    1. MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland
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  • Marko Salmi

    Corresponding author
    1. MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland
    2. Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland
    • MediCity Research Laboratory, University of Turku, Tykistökatu 6 A, FIN-20520 Turku, Finland Fax: +358-2-333-7000
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Abstract

CD73/ecto-5′-nucleotidase dephosphorylates extracellular AMP into adenosine, and it is a key enzyme in the regulation of adenosinergic signaling. The contribution of host CD73 to tumor growth and anti-tumor immunity has not been studied. Here, we show that under physiological conditions CD73-deficient mice had significantly elevated ATPase and ADPase activities in LN T cells. In a melanoma model, the growth of primary tumors and formation of metastasis were significantly attenuated in mice lacking CD73. Among tumor-infiltrating leukocytes there were fewer Tregs and mannose receptor-positive macrophages, and increased IFN-γ and NOS2 mRNA production in CD73-deficient mice. Treatment of tumor-bearing animals with soluble apyrase, an enzyme hydrolyzing ATP and ADP, significantly inhibited tumor growth and accumulation of intratumoral Tregs and mannose receptor-positive macrophages in the WT C57BL/6 mice but not in the CD73-deficient mice. Pharmacological inhibition of CD73 with α,β-methylene-adenosine-5′-diphosphate in WT mice retarded tumor progression similarly to the genetic deletion of CD73. Together these data show that increased pericellular ATP degradation in the absence of CD73 activity in the host cells is a novel mechanism controlling anti-tumor immunity and tumor progression, and that the purinergic balance can be manipulated therapeutically to inhibit tumor growth.

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