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Adenosine receptor blockade potently suppresses the metastasis of CD73+ tumours

Paul A. Beavis1*, Upulie Divisekera1, Christophe Paget1, Melvyn Chow1, Liza B. John1, John Stagg2, Mark J. Smyth1, 3, 4 and Phillip K. Darcy1*
  • 1 Peter MacCallum Cancer Centre, Australia
  • 2 Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Canada
  • 3 Queensland Institute of Medical Research, Immunology in Cancer and Infection Laboratory, Australia
  • 4 University of Queensland, School of Medicine, Australia

It is now accepted that tumours utilize multiple mechanisms to suppress anti-tumour immunity. One such mechanism is the generation of adenosine by CD73 which inhibits anti-tumour immunity through the activation of adenosine receptors expressed on multiple immune subsets [1]. Expression of CD73 enhances tumor metastasis [2], although the immune subsets and adenosine receptor subtypes involved are unknown. In this study, we revealed that both adenosine receptor 2A (A2A) and A2B antagonists significantly reduced the metastasis of CD73+ tumors. A2A/A2B receptor antagonists were effective in reducing the metastasis of tumours expressing CD73 endogenously (4T1.2) and when CD73 was ectopically expressed (B16F10). CD73-generated adenosine promoted metastasis, in part, through A2A-mediated suppression of NK cell cytotoxicity. Treatment with an A2A antagonist increased the expression of granzyme B in NK cells isolated from tumour-bearing mice and significantly reduced the metastasis of CD73+ tumours in a perforin-dependent manner. A2B blockade had no effect on NK cell cytotoxicity indicating that an NK cell-independent mechanism also contributed to the increased metastasis of CD73+ tumours. Preliminary data suggests that A2B blockade enhances the expression of MHCII on CD11b+CD11c+ cells within the metastatic site. Our data indicates that CD73 promotes tumour metastasis through multiple mechanisms including suppression of NK cell cytotoxicity and that A2A or A2B antagonists may be useful for treatment of tumour metastases. This data has potential therapeutic implications given that A2A/A2B receptor antagonists have already entered clinical trials for other therapeutic settings whereas there are no anti-CD73 mAbs currently in clinical development.




References

References
1. Beavis, P.A., et al., CD73: a potent suppressor of antitumor immune responses. Trends Immunol, 2012. 33(5): p. 231-7.
2. Stagg, J., et al., Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis. Proc Natl Acad Sci U S A, 2010. 107(4): p. 1547-52.

Keywords: CD73, adenosine receptor antagonists, metastasis, cancer immunotherapy, tumour immunology, mouse models

Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.

Presentation Type: Abstract

Topic: Translational immunology and immune intervention

Citation: Beavis PA, Divisekera U, Paget C, Chow M, John LB, Stagg J, Smyth MJ and Darcy PK (2013). Adenosine receptor blockade potently suppresses the metastasis of CD73+ tumours. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00711

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Received: 14 Jun 2013; Published Online: 22 Aug 2013.

* Correspondence:
Dr. Paul A Beavis, Peter MacCallum Cancer Centre, Melbourne, Australia, paul.beavis@petermac.org
Prof. Phillip K Darcy, Peter MacCallum Cancer Centre, Melbourne, Australia, Phil.darcy@petermac.org