Blockade of A(2A) receptors potently suppresses the metastasis of CD73(+) tumors

Beavis, Paul A., Divisekera, Upulie, Paget, Christophe, Chow, Melvyn T., John, Liza B., Devaud, Christel, Dwyer, Karen, Stagg, John, Smyth, Mark J. and Darcy, Phillip K. (2013) Blockade of A(2A) receptors potently suppresses the metastasis of CD73(+) tumors. Proceedings of the National Academy of Sciences of the United States of America, 110 36: 14711-14716. doi:10.1073/pnas.1308209110


Author Beavis, Paul A.
Divisekera, Upulie
Paget, Christophe
Chow, Melvyn T.
John, Liza B.
Devaud, Christel
Dwyer, Karen
Stagg, John
Smyth, Mark J.
Darcy, Phillip K.
Title Blockade of A(2A) receptors potently suppresses the metastasis of CD73(+) tumors
Formatted title
Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2013-09
Year available 2013
Sub-type Article (original research)
DOI 10.1073/pnas.1308209110
Open Access Status DOI
Volume 110
Issue 36
Start page 14711
End page 14716
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Collection year 2014
Language eng
Formatted 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.
Keyword Cancer metastasis
Immunotherapy
Tumor immunosuppression
Innate immunity
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Medicine Publications
 
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