Limits...
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.

Show MeSH

Related in: MedlinePlus

Anti-CD115 mAb treatment depletes TAMs and M2-type macrophages in PyMT mouse tumors.F4/80 (A, B) or CD163 (C, D) expression in mammary tumors sampled at week 14 from mice treated with either PBS (A, C) or mAb AFS98 (B, D). Staining with irrelevant isotype control is shown in E, F. Sections shown were obtained from one mouse representative of 3 analyzed per group. Blue: DNA; Red: F4/80+ (A, B) or CD163+ (C, D) macrophages. F4/80 (G) and CD163 (H) staining were quantified in the tumors from mice treated with either PBS, control rat IgG or mAb AFS98.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3760897&req=5

pone-0073310-g005: Anti-CD115 mAb treatment depletes TAMs and M2-type macrophages in PyMT mouse tumors.F4/80 (A, B) or CD163 (C, D) expression in mammary tumors sampled at week 14 from mice treated with either PBS (A, C) or mAb AFS98 (B, D). Staining with irrelevant isotype control is shown in E, F. Sections shown were obtained from one mouse representative of 3 analyzed per group. Blue: DNA; Red: F4/80+ (A, B) or CD163+ (C, D) macrophages. F4/80 (G) and CD163 (H) staining were quantified in the tumors from mice treated with either PBS, control rat IgG or mAb AFS98.

Mentions: As found in the EL4 SC tumor model, the macrophage marker F4/80 was strongly decreased in primary mammary tumors from PyMT mice treated with 50 mg/kg AFS98 sampled one week after cessation of the treatment, compared to PBS-treated mice (Figure 5A, B, G). The number of M2-polarized macrophages identified by CD163 staining was also reduced in tumors from anti-CD115-treated mice (Figure 5C, D, H). However, angiogenesis was not detectably inhibited as found by CD31 staining of these tumors, sampled one week after cessation of the treatment (data not shown).


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)

Anti-CD115 mAb treatment depletes TAMs and M2-type macrophages in PyMT mouse tumors.F4/80 (A, B) or CD163 (C, D) expression in mammary tumors sampled at week 14 from mice treated with either PBS (A, C) or mAb AFS98 (B, D). Staining with irrelevant isotype control is shown in E, F. Sections shown were obtained from one mouse representative of 3 analyzed per group. Blue: DNA; Red: F4/80+ (A, B) or CD163+ (C, D) macrophages. F4/80 (G) and CD163 (H) staining were quantified in the tumors from mice treated with either PBS, control rat IgG or mAb AFS98.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3760897&req=5

pone-0073310-g005: Anti-CD115 mAb treatment depletes TAMs and M2-type macrophages in PyMT mouse tumors.F4/80 (A, B) or CD163 (C, D) expression in mammary tumors sampled at week 14 from mice treated with either PBS (A, C) or mAb AFS98 (B, D). Staining with irrelevant isotype control is shown in E, F. Sections shown were obtained from one mouse representative of 3 analyzed per group. Blue: DNA; Red: F4/80+ (A, B) or CD163+ (C, D) macrophages. F4/80 (G) and CD163 (H) staining were quantified in the tumors from mice treated with either PBS, control rat IgG or mAb AFS98.
Mentions: As found in the EL4 SC tumor model, the macrophage marker F4/80 was strongly decreased in primary mammary tumors from PyMT mice treated with 50 mg/kg AFS98 sampled one week after cessation of the treatment, compared to PBS-treated mice (Figure 5A, B, G). The number of M2-polarized macrophages identified by CD163 staining was also reduced in tumors from anti-CD115-treated mice (Figure 5C, D, H). However, angiogenesis was not detectably inhibited as found by CD31 staining of these tumors, sampled one week after cessation of the treatment (data not shown).

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