title: 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.affiliation: Transgene, Illkirch-Graffenstaden, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fend
authors.forename: Nathalie
authors.initials: N
authors.lastname: Accart
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Kintz
authors.forename: Sandrine
authors.initials: S
authors.lastname: Cochin
authors.forename: Carine
authors.initials: C
authors.lastname: Reymann
authors.forename: Fabrice
authors.initials: F
authors.lastname: Le Pogam
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Marchand
authors.forename: Thierry
authors.initials: T
authors.lastname: Menguy
authors.forename: Philippe
authors.initials: P
authors.lastname: Slos
authors.forename: Ronald
authors.initials: R
authors.lastname: Rooke
authors.forename: Sylvie
authors.initials: S
authors.lastname: Fournel
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Bonnefoy
authors.forename: Xavier
authors.initials: X
authors.lastname: Préville
authors.forename: Hélène
authors.initials: H
authors.lastname: Haegel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000628:therapy*; D010010:Osteoclasts / Q000276:immunology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000276:immunology*; D016019:Survival Analysis
chemical_list: D000911:Antibodies, Monoclonal; D016186:Receptor, Macrophage Colony-Stimulating Factor
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