title: Altered purinergic signaling in CD73-deficient mice inhibits tumor progression.
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.
authors.affiliation: MediCity Research Laboratory, University of Turku, and National Institute of Health and Welfare, Turku, Finland.
authors.forename: Gennady G
authors.initials: GG
authors.lastname: Yegutkin
authors.forename: Fumiko
authors.initials: F
authors.lastname: Marttila-Ichihara
authors.forename: Marika
authors.initials: M
authors.lastname: Karikoski
authors.forename: Jussi
authors.initials: J
authors.lastname: Niemelä
authors.forename: Juha P
authors.initials: JP
authors.lastname: Laurila
authors.forename: Kati
authors.initials: K
authors.lastname: Elima
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001081:Apyrase / Q000378:metabolism* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D007371:Interferon-gamma / Q000235:genetics; D037181:Lectins, C-Type / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D011687:Purines / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011687:Purines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D000244:Adenosine Diphosphate; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D015720:5'-Nucleotidase; D000251:Adenosine Triphosphatases; D001081:Apyrase