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

• Published in: PloS one 2013-09, Vol.8 (9), p.e73310-e73310
• Main Authors: Fend, Laetitia, Accart, Nathalie, Kintz, Jacqueline, Cochin, Sandrine, Reymann, Carine, Le Pogam, Fabrice, Marchand, Jean-Baptiste, Menguy, Thierry, Slos, Philippe, Rooke, Ronald, Fournel, Sylvie, Bonnefoy, Jean-Yves, Préville, Xavier, Haegel, Hélène
• Format: Article
• Language: English
• Subjects: Analysis; Angiogenesis; Animal models; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - therapeutic use; Biocompatibility; Biology; Blocking antibodies; Bone cancer; Bone loss; Bone Neoplasms - secondary; Breast cancer; Breast Neoplasms - pathology; Cancer; Cancer immunotherapy; Cancer metastasis; Cancer prevention; CD163 antigen; Cell Line, Tumor; Chemotherapy; Depletion; Destruction; Differentiation; Disease Models, Animal; Female; Health aspects; Heterografts; Humans; Immunoglobulins; Immunohistochemistry; Immunotherapy; Inhibition; Kinases; Macrophage colony-stimulating factor; Macrophages; Macrophages - immunology; Medical prognosis; Medicine; Metastases; Metastasis; Mice; Mice, Inbred C57BL; Mice, Nude; Monoclonal antibodies; Myeloid cells; Neoplasms, Experimental - therapy; Osteoclastogenesis; Osteoclasts; Osteoclasts - immunology; Paclitaxel; Prostate; Receptor, Macrophage Colony-Stimulating Factor - immunology; Rodents; Survival; Survival Analysis; Tumors; Vascular endothelial growth factor
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0073310

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.