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Macrophage Susceptibility to Emactuzumab (RG7155) Treatment
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| Zeitschriftentitel: | Molecular Cancer Therapeutics |
|---|---|
| Personen und Körperschaften: | , , , , , , |
| In: | Molecular Cancer Therapeutics, 15, 2016, 12, S. 3077-3086 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
|
| Schlagwörter: |
| author_facet |
Pradel, Leon P. Ooi, Chia-Huey Romagnoli, Solange Cannarile, Michael A. Sade, Hadassah Rüttinger, Dominik Ries, Carola H. Pradel, Leon P. Ooi, Chia-Huey Romagnoli, Solange Cannarile, Michael A. Sade, Hadassah Rüttinger, Dominik Ries, Carola H. |
|---|---|
| author |
Pradel, Leon P. Ooi, Chia-Huey Romagnoli, Solange Cannarile, Michael A. Sade, Hadassah Rüttinger, Dominik Ries, Carola H. |
| spellingShingle |
Pradel, Leon P. Ooi, Chia-Huey Romagnoli, Solange Cannarile, Michael A. Sade, Hadassah Rüttinger, Dominik Ries, Carola H. Molecular Cancer Therapeutics Macrophage Susceptibility to Emactuzumab (RG7155) Treatment Cancer Research Oncology |
| author_sort |
pradel, leon p. |
| spelling |
Pradel, Leon P. Ooi, Chia-Huey Romagnoli, Solange Cannarile, Michael A. Sade, Hadassah Rüttinger, Dominik Ries, Carola H. 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-16-0157 <jats:title>Abstract</jats:title> <jats:p>Blockade of colony-stimulating factor-1 receptor (CSF-1R) enables the therapeutic targeting of tumor-associated macrophages (TAM) in cancer patients. Various CSF-1R inhibitors, mAbs, and tyrosine kinase inhibitors are currently evaluated in early clinical trials. Presence of an alternative survival signal, such as GM-CSF, rescues human monocyte-derived macrophages from CSF-1R inhibitor–induced apoptosis. In this study, we sought to identify additional factors that mediate resistance to CSF-1R–blocking antibody RG7155 (emactuzumab). We investigated the impact of hypoxia, macrophage-polarizing cytokines IL4 and IL10, and genetic alterations within the CSF1R locus and mitochondrial DNA. Among all investigated factors, only IL4 completely rescued viability of RG7155-treated macrophages in vitro. This RG7155-resistant population was characterized by a substantially increased mannose receptor-1 (CD206) expression. Analysis of CD206 and the hemoglobin scavenger receptor CD163 expression on normal tissue allowed for discrimination of distinct macrophage populations according to localization and frequency. In emactuzumab-treated cancer patients, we found a significant reduction of CSF-1R, CD204, and CD163 mRNA levels in contrast to a less pronounced decrease of CD206 expression by transcriptome analysis of tumor biopsies. However, we detected in normal skin tissue, which shows lower IL4 mRNA expression compared with melanoma tissue, significant reduction of CD206+ dermal macrophages in RG7155-treated skin biopsies. These results suggest that in cancers where the cytokines IL4 and GM-CSF are sufficiently expressed to induce very high CD206 expression on macrophages, CSF-1R inhibition may not deplete CD206hi TAM. This observation can help to identify those patients most likely to benefit from CSF-1R–targeting agents. Mol Cancer Ther; 15(12); 3077–86. ©2016 AACR.</jats:p> Macrophage Susceptibility to Emactuzumab (RG7155) Treatment Molecular Cancer Therapeutics |
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| title |
Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_unstemmed |
Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_full |
Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_fullStr |
Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_full_unstemmed |
Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_short |
Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_sort |
macrophage susceptibility to emactuzumab (rg7155) treatment |
| topic |
Cancer Research Oncology |
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http://dx.doi.org/10.1158/1535-7163.mct-16-0157 |
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2016 |
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3077-3086 |
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<jats:title>Abstract</jats:title>
<jats:p>Blockade of colony-stimulating factor-1 receptor (CSF-1R) enables the therapeutic targeting of tumor-associated macrophages (TAM) in cancer patients. Various CSF-1R inhibitors, mAbs, and tyrosine kinase inhibitors are currently evaluated in early clinical trials. Presence of an alternative survival signal, such as GM-CSF, rescues human monocyte-derived macrophages from CSF-1R inhibitor–induced apoptosis. In this study, we sought to identify additional factors that mediate resistance to CSF-1R–blocking antibody RG7155 (emactuzumab). We investigated the impact of hypoxia, macrophage-polarizing cytokines IL4 and IL10, and genetic alterations within the CSF1R locus and mitochondrial DNA. Among all investigated factors, only IL4 completely rescued viability of RG7155-treated macrophages in vitro. This RG7155-resistant population was characterized by a substantially increased mannose receptor-1 (CD206) expression. Analysis of CD206 and the hemoglobin scavenger receptor CD163 expression on normal tissue allowed for discrimination of distinct macrophage populations according to localization and frequency. In emactuzumab-treated cancer patients, we found a significant reduction of CSF-1R, CD204, and CD163 mRNA levels in contrast to a less pronounced decrease of CD206 expression by transcriptome analysis of tumor biopsies. However, we detected in normal skin tissue, which shows lower IL4 mRNA expression compared with melanoma tissue, significant reduction of CD206+ dermal macrophages in RG7155-treated skin biopsies. These results suggest that in cancers where the cytokines IL4 and GM-CSF are sufficiently expressed to induce very high CD206 expression on macrophages, CSF-1R inhibition may not deplete CD206hi TAM. This observation can help to identify those patients most likely to benefit from CSF-1R–targeting agents. Mol Cancer Ther; 15(12); 3077–86. ©2016 AACR.</jats:p> |
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| author | Pradel, Leon P., Ooi, Chia-Huey, Romagnoli, Solange, Cannarile, Michael A., Sade, Hadassah, Rüttinger, Dominik, Ries, Carola H. |
| author_facet | Pradel, Leon P., Ooi, Chia-Huey, Romagnoli, Solange, Cannarile, Michael A., Sade, Hadassah, Rüttinger, Dominik, Ries, Carola H., Pradel, Leon P., Ooi, Chia-Huey, Romagnoli, Solange, Cannarile, Michael A., Sade, Hadassah, Rüttinger, Dominik, Ries, Carola H. |
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| description | <jats:title>Abstract</jats:title> <jats:p>Blockade of colony-stimulating factor-1 receptor (CSF-1R) enables the therapeutic targeting of tumor-associated macrophages (TAM) in cancer patients. Various CSF-1R inhibitors, mAbs, and tyrosine kinase inhibitors are currently evaluated in early clinical trials. Presence of an alternative survival signal, such as GM-CSF, rescues human monocyte-derived macrophages from CSF-1R inhibitor–induced apoptosis. In this study, we sought to identify additional factors that mediate resistance to CSF-1R–blocking antibody RG7155 (emactuzumab). We investigated the impact of hypoxia, macrophage-polarizing cytokines IL4 and IL10, and genetic alterations within the CSF1R locus and mitochondrial DNA. Among all investigated factors, only IL4 completely rescued viability of RG7155-treated macrophages in vitro. This RG7155-resistant population was characterized by a substantially increased mannose receptor-1 (CD206) expression. Analysis of CD206 and the hemoglobin scavenger receptor CD163 expression on normal tissue allowed for discrimination of distinct macrophage populations according to localization and frequency. In emactuzumab-treated cancer patients, we found a significant reduction of CSF-1R, CD204, and CD163 mRNA levels in contrast to a less pronounced decrease of CD206 expression by transcriptome analysis of tumor biopsies. However, we detected in normal skin tissue, which shows lower IL4 mRNA expression compared with melanoma tissue, significant reduction of CD206+ dermal macrophages in RG7155-treated skin biopsies. These results suggest that in cancers where the cytokines IL4 and GM-CSF are sufficiently expressed to induce very high CD206 expression on macrophages, CSF-1R inhibition may not deplete CD206hi TAM. This observation can help to identify those patients most likely to benefit from CSF-1R–targeting agents. Mol Cancer Ther; 15(12); 3077–86. ©2016 AACR.</jats:p> |
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| spelling | Pradel, Leon P. Ooi, Chia-Huey Romagnoli, Solange Cannarile, Michael A. Sade, Hadassah Rüttinger, Dominik Ries, Carola H. 1535-7163 1538-8514 American Association for Cancer Research (AACR) Cancer Research Oncology http://dx.doi.org/10.1158/1535-7163.mct-16-0157 <jats:title>Abstract</jats:title> <jats:p>Blockade of colony-stimulating factor-1 receptor (CSF-1R) enables the therapeutic targeting of tumor-associated macrophages (TAM) in cancer patients. Various CSF-1R inhibitors, mAbs, and tyrosine kinase inhibitors are currently evaluated in early clinical trials. Presence of an alternative survival signal, such as GM-CSF, rescues human monocyte-derived macrophages from CSF-1R inhibitor–induced apoptosis. In this study, we sought to identify additional factors that mediate resistance to CSF-1R–blocking antibody RG7155 (emactuzumab). We investigated the impact of hypoxia, macrophage-polarizing cytokines IL4 and IL10, and genetic alterations within the CSF1R locus and mitochondrial DNA. Among all investigated factors, only IL4 completely rescued viability of RG7155-treated macrophages in vitro. This RG7155-resistant population was characterized by a substantially increased mannose receptor-1 (CD206) expression. Analysis of CD206 and the hemoglobin scavenger receptor CD163 expression on normal tissue allowed for discrimination of distinct macrophage populations according to localization and frequency. In emactuzumab-treated cancer patients, we found a significant reduction of CSF-1R, CD204, and CD163 mRNA levels in contrast to a less pronounced decrease of CD206 expression by transcriptome analysis of tumor biopsies. However, we detected in normal skin tissue, which shows lower IL4 mRNA expression compared with melanoma tissue, significant reduction of CD206+ dermal macrophages in RG7155-treated skin biopsies. These results suggest that in cancers where the cytokines IL4 and GM-CSF are sufficiently expressed to induce very high CD206 expression on macrophages, CSF-1R inhibition may not deplete CD206hi TAM. This observation can help to identify those patients most likely to benefit from CSF-1R–targeting agents. Mol Cancer Ther; 15(12); 3077–86. ©2016 AACR.</jats:p> Macrophage Susceptibility to Emactuzumab (RG7155) Treatment Molecular Cancer Therapeutics |
| spellingShingle | Pradel, Leon P., Ooi, Chia-Huey, Romagnoli, Solange, Cannarile, Michael A., Sade, Hadassah, Rüttinger, Dominik, Ries, Carola H., Molecular Cancer Therapeutics, Macrophage Susceptibility to Emactuzumab (RG7155) Treatment, Cancer Research, Oncology |
| title | Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_full | Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_fullStr | Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_full_unstemmed | Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_short | Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| title_sort | macrophage susceptibility to emactuzumab (rg7155) treatment |
| title_unstemmed | Macrophage Susceptibility to Emactuzumab (RG7155) Treatment |
| topic | Cancer Research, Oncology |
| url | http://dx.doi.org/10.1158/1535-7163.mct-16-0157 |