title: Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors.
abstract: CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown. In this study, we revealed that A2A/A2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A2A(-/-) mice were strongly protected against tumor metastasis, indicating that host A2A receptors enhanced tumor metastasis. A2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A2A blockade was due to enhanced NK cell function. Interestingly, A2B blockade had no effect on NK cell cytotoxicity, indicating that an NK cell-independent mechanism also contributed to the increased metastasis of CD73(+) tumors. Our results thus revealed that CD73 promotes tumor metastasis through multiple mechanisms, including suppression of NK cell function. Furthermore, our data strongly suggest that A2A or A2B antagonists may be useful for the treatment of metastatic disease. Overall, our study has potential therapeutic implications given that A2A/A2B receptor antagonists have already entered clinical trials in other therapeutic settings.
authors: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
authors: Paul A
authors: PA
authors: Beavis
authors: Upulie
authors: U
authors: Divisekera
authors: Christophe
authors: C
authors: Paget
authors: Melvyn T
authors: MT
authors: Chow
authors: Liza B
authors: LB
authors: John
authors: Christel
authors: C
authors: Devaud
authors: Karen
authors: K
authors: Dwyer
authors: John
authors: J
authors: Stagg
authors: Mark J
authors: MJ
authors: Smyth
authors: Phillip K
authors: PK
authors: Darcy
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000276:immunology / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
chemical_list: C518874:1-propyl-8-(4-sulfophenyl)xanthine; C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D014230:Triazoles; D014970:Xanthines; D015720:5'-Nucleotidase; D053804:Granzymes
keywords: cancer metastasis; immunotherapy; innate immunity; tumor immunosuppression
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