Activation of Tumor-Promoting Type 2 Macrophages by EGFR-Targeting Antibody Cetuximab
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Abstract
Purpose: In a recent randomized phase III clinical trial in metastatic colorectal cancer patients, the addition of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) cetuximab to bevacizumab and chemotherapy resulted in decreased progression-free survival, in particular for patients with the high-affinity FcγRIIIA. Experimental Design: The presence of natural killer (NK) cells and type 2 (M2) macrophages in colorectal cancer was determined by immunohistochemistry, using antibodies to lineage-specific markers NKp46 and CD68 with CD163, respectively. Influence of tumor-bound cetuximab on M2 macrophages was carried out in vitro with EGFR-expressing tumor cells and short-term differentiated monocytes from blood donors, who were typed for the FcγRIIIA polymorphism (CD16). Results: Antibody-dependent cellular cytotoxicity by NK cells is generally proposed as one of the antitumor mechanisms of mAbs. We found that CD163-positive M2 macrophages are much more abundant in colorectal carcinomas. In vitro analysis of M2 macrophages revealed high levels of Fc-gamma receptors (FcγR) and PD-L1 and production of IL-10 and VEGF but not IL-12. These anti-inflammatory and tumor-promoting mediators were released upon coculture with EGFR-positive tumor cells loaded with low concentrations of cetuximab. Macrophage activation depended on EGFR expression on the tumor cells, FcγRs, target specificity of the mAb and mobility of antibody complexes. Cetuximab-induced macrophage responses were more pronounced for FCGR3A 158-Val (high-affinity) carriers. Conclusion: These results suggest that tumor-promoting M2 macrophages are activated by the therapeutic mAb cetuximab in the local tumor microenvironment and argue that this immune mechanism should be taken into account for the application of therapeutic antibodies. Clin Cancer Res; 17(17); 5668–73. ©2011 AACR.
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NK cell-mediated ADCC activated by cetuximab triggers immunogenic death of tumour cells, thereby increasing the antitumour activity of immunotherapy.
“In addition, NK cell-mediated ADCC activated by cetuximab triggers immunogenic death of tumour cells, thereby increasing the antitumour activity of immunotherapy [131].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [131]
Cetuximab polarizes M2-like TAMs that express high PD-L1 and secrete IL10 and VEGFA, as seen upon ADCP in vitro.
“PD-L1 upregulation in macrophages upon ADCP in vitro”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Pander et al., 2011
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- Authors
- Pander, J., Heusinkveld, M., van der Straaten, T., Jordanova, E. S., Baak-Pablo, R., Gelderblom, H., Morreau, H., van der Burg, S. H., Guchelaar, H.-J., & van Hall, T.
- Affiliations
- Leiden University Medical Center (NL)
- Authors' Affiliations: Departments of 1Clinical Pharmacy & Toxicology, 2Clinical Oncology, and 3Pathology, Leiden University Medical Center, Leiden, the Netherlands
- Venue
- Clinical Cancer Research
- Published
- 2011-09-01
- Volume
- 17
- Issue
- 17
- Pages
- 5668-5673
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2171756567
- Cited by
- 101
- References
- 24
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 4 · 2022: 10 · 2021: 7 · 2020: 6 · 2019: 7 · 2018: 7 · 2017: 5 · 2016: 6 · 2015: 7 · 2014: 6 · 2013: 11 · 2012: 10
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- green
- research.vumc.nl
- Licence
- other-oa
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- cetuximab, M2 macrophages, colorectal cancer, FcγRIIIa polymorphism, CD16, antibody-dependent cellular cytotoxicity, natural killer cells, tumor microenvironment, macrophage activation, PD-L1, IL-10, vascular endothelial growth factor, bevacizumab
- MeSH terms
- Cetuximab, CD68 Molecule, CD163 Antigen, Antibodies, Monoclonal, Antibody-Dependent Cell Cytotoxicity, Antineoplastic Agents, Humans, Killer Cells, Natural, Macrophage Activation, Macrophages, Receptors, Cell Surface, Colorectal Neoplasms, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Interleukin-10, Receptors, IgG, Interleukin-12, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Natural Cytotoxicity Triggering Receptor 1, Tumor Microenvironment, B7-H1 Antigen, Antibodies, Monoclonal, Humanized, ErbB Receptors
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