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

Fend L, Accart N, Kintz J, Cochin S, Reymann C, Le Pogam F, Marchand JB, Menguy T, Slos P, Rooke R, Fournel S, Bonnefoy JY, Préville X, Haegel H - PLoS ONE (2013)

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.

View Article: PubMed Central - PubMed

Affiliation: Transgene, Illkirch-Graffenstaden, France.

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.

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Therapeutic and osteoclast-inhibitory effects of anti-mouse CD115 mAb in a breast cancer metastasis-induced osteolysis model.Athymic nude mice implanted with MDA-MB231 tumor cells were treated with mAb AFS98, control rat IgG (both IP at 50 mg/kg, IP 3 times a week), zoledronic acid (0.1 mg/kg) or PBS (both SC, on days 0 and 14). 7.A. Bone-protective effect of anti-CD115 mAb. Osteolytic lesions were measured at the end of the experiment. Left: Total osteolytic lesion areas (mm2, mean+SD) are shown as the sums of the areas of the bone lesions in right and left tibia and femur. Right: Number of osteolytic lesions (mean+SD). The results are shown as the counts of individual bone lesions in right and left tibia and femur. 7.B. Osteoclast-inhibitory effect of anti-CD115 mAb. Left: The osteoclast marker TRACP 5b was titrated in serum sampled at day 24. Results are expressed as relative change (%) in serum TRACP 5b from day 0 to day 24 (mean+SD). Right: Sections from hind limbs of each animal were stained for TRACP 5b and osteoclast numbered at the tumor-bone interface (mean+SD). Osteoclast numbers were divided by the length of this interface. 7.C. Effects of anti-CD115 mAb on trabecular bone and inhibition of cancer-induced weight loss. Left: Trabecular bone area (mm2, mean+SD) of each animal was determined by histomorphometry. The results shown are the sums of trabecular bone areas in right and left tibia and femur. Right: Relative body weight at sacrifice (%, relative to day 0, mean+SD). *p<0.05; **p<0.01 and ***p<0.001 compared with control, using the statistical tests indicated in Materials and Methods.
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pone-0073310-g007: Therapeutic and osteoclast-inhibitory effects of anti-mouse CD115 mAb in a breast cancer metastasis-induced osteolysis model.Athymic nude mice implanted with MDA-MB231 tumor cells were treated with mAb AFS98, control rat IgG (both IP at 50 mg/kg, IP 3 times a week), zoledronic acid (0.1 mg/kg) or PBS (both SC, on days 0 and 14). 7.A. Bone-protective effect of anti-CD115 mAb. Osteolytic lesions were measured at the end of the experiment. Left: Total osteolytic lesion areas (mm2, mean+SD) are shown as the sums of the areas of the bone lesions in right and left tibia and femur. Right: Number of osteolytic lesions (mean+SD). The results are shown as the counts of individual bone lesions in right and left tibia and femur. 7.B. Osteoclast-inhibitory effect of anti-CD115 mAb. Left: The osteoclast marker TRACP 5b was titrated in serum sampled at day 24. Results are expressed as relative change (%) in serum TRACP 5b from day 0 to day 24 (mean+SD). Right: Sections from hind limbs of each animal were stained for TRACP 5b and osteoclast numbered at the tumor-bone interface (mean+SD). Osteoclast numbers were divided by the length of this interface. 7.C. Effects of anti-CD115 mAb on trabecular bone and inhibition of cancer-induced weight loss. Left: Trabecular bone area (mm2, mean+SD) of each animal was determined by histomorphometry. The results shown are the sums of trabecular bone areas in right and left tibia and femur. Right: Relative body weight at sacrifice (%, relative to day 0, mean+SD). *p<0.05; **p<0.01 and ***p<0.001 compared with control, using the statistical tests indicated in Materials and Methods.

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 [37], [41]. MDA-MB231 cells are known to secrete human CSF-1 [42], which can activate murine CD115 [7]. MDA-MB231 cells are reported to also express human CD115 [42], but mAb AFS98 is specific for murine CD115 [34]; 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 [37]. 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.


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

Fend L, Accart N, Kintz J, Cochin S, Reymann C, Le Pogam F, Marchand JB, Menguy T, Slos P, Rooke R, Fournel S, Bonnefoy JY, Préville X, Haegel H - PLoS ONE (2013)

Therapeutic and osteoclast-inhibitory effects of anti-mouse CD115 mAb in a breast cancer metastasis-induced osteolysis model.Athymic nude mice implanted with MDA-MB231 tumor cells were treated with mAb AFS98, control rat IgG (both IP at 50 mg/kg, IP 3 times a week), zoledronic acid (0.1 mg/kg) or PBS (both SC, on days 0 and 14). 7.A. Bone-protective effect of anti-CD115 mAb. Osteolytic lesions were measured at the end of the experiment. Left: Total osteolytic lesion areas (mm2, mean+SD) are shown as the sums of the areas of the bone lesions in right and left tibia and femur. Right: Number of osteolytic lesions (mean+SD). The results are shown as the counts of individual bone lesions in right and left tibia and femur. 7.B. Osteoclast-inhibitory effect of anti-CD115 mAb. Left: The osteoclast marker TRACP 5b was titrated in serum sampled at day 24. Results are expressed as relative change (%) in serum TRACP 5b from day 0 to day 24 (mean+SD). Right: Sections from hind limbs of each animal were stained for TRACP 5b and osteoclast numbered at the tumor-bone interface (mean+SD). Osteoclast numbers were divided by the length of this interface. 7.C. Effects of anti-CD115 mAb on trabecular bone and inhibition of cancer-induced weight loss. Left: Trabecular bone area (mm2, mean+SD) of each animal was determined by histomorphometry. The results shown are the sums of trabecular bone areas in right and left tibia and femur. Right: Relative body weight at sacrifice (%, relative to day 0, mean+SD). *p<0.05; **p<0.01 and ***p<0.001 compared with control, using the statistical tests indicated in Materials and Methods.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3760897&req=5

pone-0073310-g007: Therapeutic and osteoclast-inhibitory effects of anti-mouse CD115 mAb in a breast cancer metastasis-induced osteolysis model.Athymic nude mice implanted with MDA-MB231 tumor cells were treated with mAb AFS98, control rat IgG (both IP at 50 mg/kg, IP 3 times a week), zoledronic acid (0.1 mg/kg) or PBS (both SC, on days 0 and 14). 7.A. Bone-protective effect of anti-CD115 mAb. Osteolytic lesions were measured at the end of the experiment. Left: Total osteolytic lesion areas (mm2, mean+SD) are shown as the sums of the areas of the bone lesions in right and left tibia and femur. Right: Number of osteolytic lesions (mean+SD). The results are shown as the counts of individual bone lesions in right and left tibia and femur. 7.B. Osteoclast-inhibitory effect of anti-CD115 mAb. Left: The osteoclast marker TRACP 5b was titrated in serum sampled at day 24. Results are expressed as relative change (%) in serum TRACP 5b from day 0 to day 24 (mean+SD). Right: Sections from hind limbs of each animal were stained for TRACP 5b and osteoclast numbered at the tumor-bone interface (mean+SD). Osteoclast numbers were divided by the length of this interface. 7.C. Effects of anti-CD115 mAb on trabecular bone and inhibition of cancer-induced weight loss. Left: Trabecular bone area (mm2, mean+SD) of each animal was determined by histomorphometry. The results shown are the sums of trabecular bone areas in right and left tibia and femur. Right: Relative body weight at sacrifice (%, relative to day 0, mean+SD). *p<0.05; **p<0.01 and ***p<0.001 compared with control, using the statistical tests indicated in Materials and Methods.
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 [37], [41]. MDA-MB231 cells are known to secrete human CSF-1 [42], which can activate murine CD115 [7]. MDA-MB231 cells are reported to also express human CD115 [42], but mAb AFS98 is specific for murine CD115 [34]; 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 [37]. 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.

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.

View Article: PubMed Central - PubMed

Affiliation: Transgene, Illkirch-Graffenstaden, France.

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.

Show MeSH
Related in: MedlinePlus