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 aimed at studying the effect of anti-CD115 mAb treatment on the development of these mammary tumors. On tumor sections at the EC stage, all F4/80-positive infiltrating macrophages were stained with an anti-CD115 antibody (Figure S3). In contrast, PyMT tumor cells do not express CD115  and therefore cannot be directly targeted by AFS98 treatment. The mAb was administered (50 mg/kg, IP 3 times per week) to PyMT mice from week 10 to 13, at the time of MIN to EC transition (Figure 3). Palpable mammary tumors appeared significantly later (15.8+/−0.9 weeks, n = 10) than in mice treated with isotype control (13.8+/−1.4 weeks, p = 0.0112, n = 10) or with PBS (14.4+/−1.1 weeks, p = 0.020, n = 10) (Figure 4A). Tumor sizes were significantly reduced with AFS98 at week 13 (p = 0.0149 vs PBS and p = 0.0098 vs rat IgG) and at week 14, after termination of the treatment (p = 0.0183 vs rat IgG- and p = 0.0212 vs PBS-treated mice) (Figure 4B). AFS98 treatment significantly prolonged survival when compared with rat IgG (p = 0.018) (Figure 4C). Of note, treatment with rat IgG had a deleterious effect on survival when compared to the PBS-treated group (p = 0.0283). The therapeutic effect of the anti-CD115 mAb was lost two weeks after cessation of the treatment. This may be explained by the dramatic upregulation of circulating CSF-1, occurring in C57BL/6 (Figure S2) and in PyMT mice (data not shown) following multiple mAb administration.