Anti-CD73 antibody therapy inhibits breast tumor growth and metastasis

• DOI: 10.1073/pnas.0908801107
• Publication Date: 2010-01-05T02:36:36Z
• Authors: John Stagg; Upulie Divisekera; Nicole McLaughlin; Janelle Sharkey; Sandra Pommey; Delphine Denoyer; Karen M. Dwyer; Mark J. Smyth
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Adenosine; Antibodies, Neoplasm; Chemotaxis; Antibodies, Monoclonal; Breast Neoplasms; Mice, SCID; Regulatory; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Cell Movement; 1000 General; Cell Line, Tumor; Disease Progression; Animals; Female; Neoplasm Metastasis; 5'-Nucleotidase; Immunosuppression; Neoplasm Transplantation; Cancer

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.