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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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Appearance and progression of palpable mammary tumors are delayed in PyMT mice treated with AFS98.At 10 weeks of age, MMTV-PyMT mice were treated with 50 mg/kg of mAb AFS98, control rat IgG or PBS, injected IP 3 times per week from week 10 to week 13. A. The appearance of palpable tumors was delayed in AFS98-treated mice. The mean age (in weeks ± SEM) of palpable tumor detection is shown for each of the 3 mouse groups. * Mann-Whitney’s test p<0.05 compared with Rat IgG and PBS-treated mouse group (n = 10). B. Tumor volumes are shown as means ± SEM. * significant difference in tumor volume using Mann-Whitney’s test, p<0.05 between groups treated with Rat IgG and PBS (n = 15). C. Percentages of surviving mice in each group. * Log-rank test p<0.05 compared with the indicated mouse group (n = 10).
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pone-0073310-g004: Appearance and progression of palpable mammary tumors are delayed in PyMT mice treated with AFS98.At 10 weeks of age, MMTV-PyMT mice were treated with 50 mg/kg of mAb AFS98, control rat IgG or PBS, injected IP 3 times per week from week 10 to week 13. A. The appearance of palpable tumors was delayed in AFS98-treated mice. The mean age (in weeks ± SEM) of palpable tumor detection is shown for each of the 3 mouse groups. * Mann-Whitney’s test p<0.05 compared with Rat IgG and PBS-treated mouse group (n = 10). B. Tumor volumes are shown as means ± SEM. * significant difference in tumor volume using Mann-Whitney’s test, p<0.05 between groups treated with Rat IgG and PBS (n = 15). C. Percentages of surviving mice in each group. * Log-rank test p<0.05 compared with the indicated mouse group (n = 10).

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 [16] 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.


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)

Appearance and progression of palpable mammary tumors are delayed in PyMT mice treated with AFS98.At 10 weeks of age, MMTV-PyMT mice were treated with 50 mg/kg of mAb AFS98, control rat IgG or PBS, injected IP 3 times per week from week 10 to week 13. A. The appearance of palpable tumors was delayed in AFS98-treated mice. The mean age (in weeks ± SEM) of palpable tumor detection is shown for each of the 3 mouse groups. * Mann-Whitney’s test p<0.05 compared with Rat IgG and PBS-treated mouse group (n = 10). B. Tumor volumes are shown as means ± SEM. * significant difference in tumor volume using Mann-Whitney’s test, p<0.05 between groups treated with Rat IgG and PBS (n = 15). C. Percentages of surviving mice in each group. * Log-rank test p<0.05 compared with the indicated mouse group (n = 10).
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pone-0073310-g004: Appearance and progression of palpable mammary tumors are delayed in PyMT mice treated with AFS98.At 10 weeks of age, MMTV-PyMT mice were treated with 50 mg/kg of mAb AFS98, control rat IgG or PBS, injected IP 3 times per week from week 10 to week 13. A. The appearance of palpable tumors was delayed in AFS98-treated mice. The mean age (in weeks ± SEM) of palpable tumor detection is shown for each of the 3 mouse groups. * Mann-Whitney’s test p<0.05 compared with Rat IgG and PBS-treated mouse group (n = 10). B. Tumor volumes are shown as means ± SEM. * significant difference in tumor volume using Mann-Whitney’s test, p<0.05 between groups treated with Rat IgG and PBS (n = 15). C. Percentages of surviving mice in each group. * Log-rank test p<0.05 compared with the indicated mouse group (n = 10).
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 [16] 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.

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