Anti-human CD73 monoclonal antibody inhibits metastasis formation in human breast cancer by inducing clustering and internalization of CD73 expressed on the surface of cancer cells
- Authors:
-
- Terp, Mikkel G ;
- Olesen, Kristina A ;
- Christensen, Eva Arnspang ;
- Lund, Rikke R ;
- Lagerholm, B Christoffer ;
- Ditzel, Henrik J ;
-
Leth-Larsen, Rikke
Close
0000-0002-1612-4089
Ditzel group, Department of Molecular Medicine, Faculty of Health Sciences, SDU
- DOI:
- 10.4049/jimmunol.1301274
- Abstract:
- Recent studies have shown that Abs that target the cell-surface enzyme CD73 (ecto-5'-nucleotidase) reduce growth of primary tumors and metastasis in syngenic mice by inhibiting the catalytic activity of CD73, and thus increasing the activity of cytotoxic T lymphocytes. In this article, we report another anticancer mechanism of anti-CD73 Abs and show that an anti-CD73 mAb (AD2) inhibits metastasis formation by a mechanism independent of CD73 catalytic activity and inhibition of primary tumor growth. This mechanism involves clustering and internalization of CD73, but does not require cross-linking of CD73, because both whole IgG anti-CD73 AD2 mAb and Fab' fragments thereof exhibited this effect. Ex vivo treatment of different breast cancer cell lines with anti-CD73 AD2 mAb before i.v. injection into mice inhibited extravasation/colonization of circulating tumor cells and significantly reduced metastasis development. This effect was also observed when the cancer cell-surface expression of CD73 was significantly reduced by small interfering RNA knockdown. The antimetastatic activity is epitope specific, as another Ab that efficiently binds CD73-expressing live cancer cells did not lead to CD73 internalization and metastasis inhibition. Furthermore, anti-CD73 AD2 mAb inhibited development of metastasis in a spontaneous animal model of human metastatic breast cancer. Our study shows that some anti-CD73 mAbs cause cell-surface clustering of CD73 followed by internalization, thus inhibiting the ability of circulating tumor cells to extravasate and colonize, leading to inhibition of metastasis. Ab-based CD73 cancer therapy should include a combination of Abs that target the catalytic activity of CD73, as well as those with the characteristics described in this article.
- Type:
- Journal article
- Language:
- English
- Published in:
- Journal of Immunology, 2013, Vol 191, Issue 8, p. 4165-4173
- Keywords:
- 5'-Nucleotidase; Animals; Antibodies, Monoclonal; Biological Transport; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Female; Humans; Immunoglobulin Fab Fragments; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Neoplastic Cells, Circulating; RNA Interference; RNA, Small Interfering; Xenograft Model Antitumor Assays
- Main Research Area:
- Medical science
- Publication Status:
- Published
- Review type:
- Peer Review
- Submission year:
- 2013
- Scientific Level:
- Scientific
- ID:
- 248807812
