Therapeutic effects of anti-CD115 monoclonal antibody in mouse cancer models through dual inhibition of tumor-associated macrophages and osteoclasts.

Abstract

Tumor progression is promoted by Tumor-Associated Macrophages (TAMs) and metastasis-induced bone destruction by osteoclasts. Both myeloid cell types depend on the CD115-CSF-1 pathway for their differentiation and function. We used 3 different mouse cancer models to study the effects of targeting cancer host myeloid cells with a monoclonal antibody (mAb) capable of blocking CSF-1 binding to murine CD115. In mice bearing sub-cutaneous EL4 tumors, which are CD115-negative, the anti-CD115 mAb depleted F4/80(+) CD163(+) M2-type TAMs and reduced tumor growth, resulting in prolonged survival. In the MMTV-PyMT mouse model, the spontaneous appearance of palpable mammary tumors was delayed when the anti-CD115 mAb was administered before malignant transition and tumors became palpable only after termination of the immunotherapy. When administered to mice already bearing established PyMT tumors, anti-CD115 treatment prolonged their survival and potentiated the effect of chemotherapy with Paclitaxel. As shown by immunohistochemistry, this therapeutic effect correlated with the depletion of F4/80(+)CD163(+) M2-polarized TAMs. In a breast cancer model of bone metastasis, the anti-CD115 mAb potently blocked the differentiation of osteoclasts and their bone destruction activity. This resulted in the inhibition of cancer-induced weight loss. CD115 thus represents a promising target for cancer immunotherapy, since a specific blocking antibody may not only inhibit the growth of a primary tumor through TAM depletion, but also metastasis-induced bone destruction through osteoclast inhibition.

• Authors: Laetitia Fend, Nathalie Accart, Jacqueline Kintz, Sandrine Cochin, Carine Reymann, Fabrice Le Pogam, Jean-Baptiste Marchand, Thierry Menguy, Philippe Slos, Ronald Rooke, Sylvie Fournel, Jean-Yves Bonnefoy, Xavier Préville, Hélène Haegel
• Journal: PloS one (PLoS One) Vol. 8 Issue 9 Pg. e73310 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24019914 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Receptor, Macrophage Colony-Stimulating Factor

Topics

• Animals
• Antibodies, Monoclonal (immunology, therapeutic use)
• Bone Neoplasms (secondary)
• Breast Neoplasms (pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Heterografts
• Humans
• Macrophages (immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Nude
• Neoplasms, Experimental (therapy)
• Osteoclasts (immunology)
• Receptor, Macrophage Colony-Stimulating Factor (immunology)
• Survival Analysis