title: Macrophage Susceptibility to Emactuzumab (RG7155) Treatment.
abstract: 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 CD206hiTAM. 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.
authors: Roche Innovation Center Munich, Discovery Oncology Roche Pharmaceutical Research and Early Development, Penzberg, Germany.|Paris Lodron University Salzburg, Natural Sciences Faculty, Salzburg, Austria.
authors: Leon P
authors: LP
authors: Pradel
authors: Roche Innovation Center Basel, Pharmaceutical Research and Early Development, Basel, Switzerland.
authors: Chia-Huey
authors: CH
authors: Ooi
authors: Roche Diagnostics, Global Business Development Division, Biomarker Programs, Basel, Switzerland.
authors: Solange
authors: S
authors: Romagnoli
authors: Roche Innovation Center Munich, Discovery Oncology Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors: Michael A
authors: MA
authors: Cannarile
authors: Roche Innovation Center Munich, Discovery Oncology Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors: Hadassah
authors: H
authors: Sade
authors: Roche Innovation Center Munich, Discovery Oncology Roche Pharmaceutical Research and Early Development, Penzberg, Germany.
authors: Dominik
authors: D
authors: Rüttinger
authors: Roche Innovation Center Munich, Discovery Oncology Roche Pharmaceutical Research and Early Development, Penzberg, Germany. carola.ries@roche.com.
authors: Carola H
authors: CH
authors: Ries
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D001706:Biopsy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D016130:Immunophenotyping; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000166:cytology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015415:Biomarkers; D016207:Cytokines; D050794:STAT1 Transcription Factor; C000602304:emactuzumab