Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis.

Abstract

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.

• Authors: John Stagg, Upulie Divisekera, Nicole McLaughlin, Janelle Sharkey, Sandra Pommey, Delphine Denoyer, Karen M Dwyer, Mark J Smyth
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 107 Issue 4 Pg. 1547-52 (Jan 26 2010) ISSN: 1091-6490 [Electronic] United States
• PMID: 20080644 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neoplasm
• 5'-Nucleotidase

Topics

• 5'-Nucleotidase (genetics, immunology)
• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Antibodies, Neoplasm (immunology, therapeutic use)
• Breast Neoplasms (immunology, pathology, therapy)
• Cell Line, Tumor
• Cell Movement
• Disease Progression
• Female
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, SCID
• Neoplasm Metastasis
• Neoplasm Transplantation