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.

The Promotion of Breast Cancer Metastasis Caused by Inhibition of CSF-1R/CSF-1 Signaling Is Blocked by Targeting the G-CSF Receptor

“…In the transgenic MMTV-PyMT mouse, studies targeting CSF-1R signaling showed contrasting results. In one study, there was no effect on primary tumor growth or metastasis (45); in another study, it reduced primary tumor growth, with no data reported for metastasis (52). Our data showed for the first time that CSF-1R and CSF-1 blockade actually enhanced metastasis in two different preclinical tumor models, providing evidence that such treatment can lead to different outcomes in different breast tumors.…”

“…TAMs TANs Cells/g of tumor ×10 6 Cells/g of tumor ×10 6 Cells/g of tumor ×10 6 Cells/g of tumor ×10 6 Cells/g of lung ×10 6 Cells/g of lung ×10 6 Cells/g of lung ×10 6 Cells/g of lung the more clinically relevant models using immunocompetent mice, anti-CSF-1R has been reported to reduce primary tumor growth (52), and reduce spontaneous metastasis in an osteosarcoma model (51). In the transgenic MMTV-PyMT mouse, studies targeting CSF-1R signaling showed contrasting results.…”

Primary Tumors Limit Metastasis Formation through Induction of IL15-Mediated Cross-Talk between Patrolling Monocytes and NK Cells

“…S4D; refs. [28][29][30]. The kinetics of these myeloid populations, including monocyte subsets and macrophages, mirrored that of NK cells, suggesting they might cooperate in preventing metastasis formation in primary tumor-bearing mice.…”

Lessons from patient-derived xenografts for better in vitro modeling of human cancer

“…Furthermore, the presence of M2 macrophages is also correlated with other signs of tumor progression, such as elevated regulatory T cell counts, induction of angiogenesis, and increase in lymph node metastasis [168][169][170]. A number of experimental approaches targeting M2 macrophage involvement in cancer have shown initial efficacy in vivo and further validate the importance of their presence in the tumor microenvironment [171][172][173][174].…”