Details

Autor(en) / Beteiligte

• Stagg, John
• Divisekera, Upulie
• McLaughlin, Nicole
• Sharkey, Janelle
• Pommey, Sandra
• Denoyer, Delphine
• Dwyer, Karen M
• Smyth, Mark J

Titel

Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2010-01, Vol.107 (4), p.1547-1552

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2010

Quelle

MEDLINE

Beschreibungen/Notizen

• Extracellular adenosine is a potent immunosuppressor that accumulates during tumor growth. We performed proof-of-concept studies investigating the therapeutic potential and mechanism of action of monoclonal antibody (mAb)-based therapy against CD73, an ecto-enzyme overexpressed on breast-cancer cells that catalyzes the dephosphorylation of adenosine monophosphates into adenosine. We showed that anti-CD73 mAb therapy significantly delayed primary 4T1.2 and E0771 tumor growth in immune-competent mice and significantly inhibited the development of spontaneous 4T1.2 lung metastases. Notably, anti-CD73 mAb therapy was essentially dependent on the induction of adaptive anti-tumor immune responses. Knockdown of CD73 in 4T1.2 tumor cells confirmed the tumor-promoting effects of CD73. In addition to its immunosuppressive effect, CD73 enhanced tumor-cell chemotaxis, suggesting a role for CD73-derived adenosine in tumor metastasis. Accordingly, administration of adenosine-5'-N-ethylcarboxamide to tumor-bearing mice significantly enhanced spontaneous 4T1.2 lung metastasis. Using selective adenosine-receptor antagonists, we showed that activation of A2B adenosine receptors promoted 4T1.2 tumor-cell chemotaxis in vitro and metastasis in vivo. In conclusion, our study identified tumor-derived CD73 as a mechanism of tumor immune escape and tumor metastasis, and it also established the proof of concept that targeted therapy against CD73 can trigger adaptive anti-tumor immunity and inhibit metastasis of breast cancer.