Therapeutic effects of anti-CD115 monoclonal antibody in mouse cancer models through dual inhibition of tumor-associated macrophages and osteoclasts.
Bottom Line: 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.
Affiliation: Transgene, Illkirch-Graffenstaden, France.
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.
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Mentions: We investigated the effect of CD115 blockade on metastasis-induced osteoclastic bone degradation. To this end, we made use of a model in which human breast cancer cells are injected in the left cardiac ventricles of athymic mice to induce osteolytic bone metastasis , . MDA-MB231 cells are known to secrete human CSF-1 , which can activate murine CD115 . MDA-MB231 cells are reported to also express human CD115 , but mAb AFS98 is specific for murine CD115 ; therefore, in this model, anti-CD115 mAb treatment will only target the murine myeloid cell compartment. Treatment of mice with 50 mg/kg mAb AFS98 potently inhibited the development of the osteolytic lesions visualized by X-ray radiography (Figure 7A). AFS98 displayed an activity similar to zoledronic acid, a standart-of-care inhibitor of osteolysis which was used as positive control. Both compounds diminished the area as well as the number of osteoclastic lesions, compared with PBS or rat IgG controls. AFS98 and zoledronic acid were equally potent at decreasing osteoclast numbers, as shown by the osteoclast marker Tartrate-resistant acid phosphatase 5b (TRACP 5b) which was diminished in the serum of mice at days 17 (data not shown) and 24 (Figure 7B). As measured by histomorphometry, osteoclast numbers at the tumor-bone interface were strongly decreased by AFS98 or zoledronic acid. Both compounds increased total and trabecular bone areas, with a stronger effect of zoledronic acid on trabecular bone areas (Figure 7C). Cancer-associated weight loss was inhibited similarly by zoledronic acid or AFS98. The MDA-MB231 cell line used in this study stably expresses GFP . Whole body tumor burden analyzed by fluorescence imaging was not modified by either anti-CD115 mAb or zoledronic acid treatment, compared with control animals (data not shown). Altogether, these results show that the anti-CD115 mAb inhibits metastasis-induced bone destruction by targeting osteoclasts.