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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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Depletion of M2-polarized TAMs by anti-mouse CD115 mAb in EL4 solid tumors.EL-4 tumors sampled at day 20 from mice treated with either PBS (A, C, E) or 50 mg/kg mAb AFS98 (B, D, F) were analyzed by IF with anti-F4/80 mAb (A, B), anti-CD163 mAb (C, D) or irrelevant isotype control (E, F). Blue : DNA; Red : F4/80+ macrophages (A, B) or CD163+ M2-type macrophages (C, D). Sections shown were obtained from one tumor representative of 3 analyzed per group. F4/80 (G) and CD163 (H) staining were quantified in the tumors shown in A-D.
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pone-0073310-g002: Depletion of M2-polarized TAMs by anti-mouse CD115 mAb in EL4 solid tumors.EL-4 tumors sampled at day 20 from mice treated with either PBS (A, C, E) or 50 mg/kg mAb AFS98 (B, D, F) were analyzed by IF with anti-F4/80 mAb (A, B), anti-CD163 mAb (C, D) or irrelevant isotype control (E, F). Blue : DNA; Red : F4/80+ macrophages (A, B) or CD163+ M2-type macrophages (C, D). Sections shown were obtained from one tumor representative of 3 analyzed per group. F4/80 (G) and CD163 (H) staining were quantified in the tumors shown in A-D.

Mentions: The effect of targeting CD115 with mAb AFS98 on tumor growth was first studied in a cancer model using EL4 thymoma cells implanted subcutaneously in the flanks of C57BL/6 mice. EL4 cells are CD115-negative in vitro as determined by IC/FC with mAb AFS98 (data not shown). Tumor growth was retarded in mice treated for 3 weeks with the anti-CD115 mAb starting ten days after implantation, compared to PBS-treated mice (Figure 1A). Only the maximal tested dose of 50 mg/kg produced a statistically significant reduction in tumor sizes (p = 0.0245 and p = 0.0166 (n = 15) at days 23 and 27, respectively), while there was no effect with 10 or 25 mg/kg. Consequently, survival was significantly prolonged (p = 0.0368) only in mice treated with 50 mg/kg AFS98 (Figure 1B). F4/80 staining by IHC showed that the macrophage population was strongly reduced in tumors sampled during AFS98 treatment, both at days 20 (Figure 2A, B) and 27 (data not shown). Expression of the M2-type macrophage marker CD163 was also considerably decreased in EL4 tumors from mice treated with 50 mg/kg AFS98 (Figure 2C, D). These results suggest that the therapeutic effect of the anti-CD115 mAb in this tumor model may be a consequence of M2-type TAM depletion.


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)

Depletion of M2-polarized TAMs by anti-mouse CD115 mAb in EL4 solid tumors.EL-4 tumors sampled at day 20 from mice treated with either PBS (A, C, E) or 50 mg/kg mAb AFS98 (B, D, F) were analyzed by IF with anti-F4/80 mAb (A, B), anti-CD163 mAb (C, D) or irrelevant isotype control (E, F). Blue : DNA; Red : F4/80+ macrophages (A, B) or CD163+ M2-type macrophages (C, D). Sections shown were obtained from one tumor representative of 3 analyzed per group. F4/80 (G) and CD163 (H) staining were quantified in the tumors shown in A-D.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3760897&req=5

pone-0073310-g002: Depletion of M2-polarized TAMs by anti-mouse CD115 mAb in EL4 solid tumors.EL-4 tumors sampled at day 20 from mice treated with either PBS (A, C, E) or 50 mg/kg mAb AFS98 (B, D, F) were analyzed by IF with anti-F4/80 mAb (A, B), anti-CD163 mAb (C, D) or irrelevant isotype control (E, F). Blue : DNA; Red : F4/80+ macrophages (A, B) or CD163+ M2-type macrophages (C, D). Sections shown were obtained from one tumor representative of 3 analyzed per group. F4/80 (G) and CD163 (H) staining were quantified in the tumors shown in A-D.
Mentions: The effect of targeting CD115 with mAb AFS98 on tumor growth was first studied in a cancer model using EL4 thymoma cells implanted subcutaneously in the flanks of C57BL/6 mice. EL4 cells are CD115-negative in vitro as determined by IC/FC with mAb AFS98 (data not shown). Tumor growth was retarded in mice treated for 3 weeks with the anti-CD115 mAb starting ten days after implantation, compared to PBS-treated mice (Figure 1A). Only the maximal tested dose of 50 mg/kg produced a statistically significant reduction in tumor sizes (p = 0.0245 and p = 0.0166 (n = 15) at days 23 and 27, respectively), while there was no effect with 10 or 25 mg/kg. Consequently, survival was significantly prolonged (p = 0.0368) only in mice treated with 50 mg/kg AFS98 (Figure 1B). F4/80 staining by IHC showed that the macrophage population was strongly reduced in tumors sampled during AFS98 treatment, both at days 20 (Figure 2A, B) and 27 (data not shown). Expression of the M2-type macrophage marker CD163 was also considerably decreased in EL4 tumors from mice treated with 50 mg/kg AFS98 (Figure 2C, D). These results suggest that the therapeutic effect of the anti-CD115 mAb in this tumor model may be a consequence of M2-type TAM depletion.

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