Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors

被引:298
作者
Beavis, Paul A. [1 ,2 ]
Divisekera, Upulie [1 ,2 ]
Paget, Christophe [1 ,2 ]
Chow, Melvyn T. [1 ,2 ]
John, Liza B. [1 ,2 ]
Devaud, Christel [1 ,2 ]
Dwyer, Karen [3 ,4 ]
Stagg, John [5 ,6 ]
Smyth, Mark J. [1 ,2 ,7 ,8 ]
Darcy, Phillip K. [1 ,2 ]
机构
[1] Peter MacCallum Canc Ctr, Canc Immunol Program, East Melbourne, Vic 3002, Australia
[2] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia
[3] St Vincents Hosp, Immunol Res Ctr, Fitzroy, Vic 3065, Australia
[4] Univ Melbourne, Dept Med, Melbourne, Vic 3010, Australia
[5] Ctr Hosp Univ Montreal, Fac Pharm, Ctr Rech, Montreal, PQ H2L 4M1, Canada
[6] Univ Montreal, Inst Canc Montreal, Montreal, PQ H2L 4M1, Canada
[7] Queensland Inst Med Res, Immunol Canc & Infect Lab, Herston, Qld 4006, Australia
[8] Univ Queensland, Sch Med, Herston, Qld 4006, Australia
基金
澳大利亚国家健康与医学研究理事会; 英国医学研究理事会; 加拿大健康研究院;
关键词
cancer metastasis; immunotherapy; tumor immunosuppression; innate immunity; A2A ADENOSINE RECEPTOR; T-CELL; LYMPHOCYTE BINDING; CANCER; A(2B); EXPRESSION; ADHESION; GROWTH; INHIBITION; ACTIVATION;
D O I
10.1073/pnas.1308209110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 A(2A)/A(2B) 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). A(2A)(-/-) mice were strongly protected against tumor metastasis, indicating that host A(2A) receptors enhanced tumor metastasis. A(2A) 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 A(2A) blockade was due to enhanced NK cell function. Interestingly, A(2B) 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 A(2A) or A(2B) antagonists may be useful for the treatment of metastatic disease. Overall, our study has potential therapeutic implications given that A(2A)/A(2B) receptor antagonists have already entered clinical trials in other therapeutic settings.
引用
收藏
页码:14711 / 14716
页数:6
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