Macrophages eliminate circulating tumor cells after monoclonal antibody therapy
Nuray Gül, … , Paul Kubes, Marjolein van Egmond
Nuray Gül, … , Paul Kubes, Marjolein van Egmond
Published February 3, 2014; First published January 16, 2014
Citation Information: J Clin Invest. 2014;124(2):812-823. https://doi.org/10.1172/JCI66776.
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Research Article Immunology

Macrophages eliminate circulating tumor cells after monoclonal antibody therapy

Abstract

The use of monoclonal antibodies (mAbs) as therapeutic tools has increased dramatically in the last decade and is now one of the mainstream strategies to treat cancer. Nonetheless, it is still not completely understood how mAbs mediate tumor cell elimination or the effector cells that are involved. Using intravital microscopy, we found that antibody-dependent phagocytosis (ADPh) by macrophages is a prominent mechanism for removal of tumor cells from the circulation in a murine tumor cell opsonization model. Tumor cells were rapidly recognized and arrested by liver macrophages (Kupffer cells). In the absence of mAbs, Kupffer cells sampled tumor cells; however, this sampling was not sufficient for elimination. By contrast, antitumor mAb treatment resulted in rapid phagocytosis of tumor cells by Kupffer cells that was dependent on the high-affinity IgG-binding Fc receptor (FcγRI) and the low-affinity IgG-binding Fc receptor (FcγRIV). Uptake and intracellular degradation were independent of reactive oxygen or nitrogen species production. Importantly, ADPh prevented the development of liver metastases. Tumor cell capture and therapeutic efficacy were lost after Kupffer cell depletion. Our data indicate that macrophages play a prominent role in mAb-mediated eradication of tumor cells. These findings may help to optimize mAb therapeutic strategies for patients with cancer by helping us to aim to enhance macrophage recruitment and activity.

Authors

Nuray Gül, Liane Babes, Kerstin Siegmund, Rianne Korthouwer, Marijn Bögels, Rens Braster, Gestur Vidarsson, Timo L.M. ten Hagen, Paul Kubes, Marjolein van Egmond

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Figure 7

Anti-EGFR mAbs induce ADPh of human epithelial carcinoma A431 cells by macrophages.

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Anti-EGFR mAbs induce ADPh of human epithelial carcinoma A431 cells by m...
(A and B) Phagocytosis of DiB-labeled (blue) B16F10gp75 cells by LysoID-labeled (red) macrophages in the presence of (A) anti-EGFR mAbs or (B) anti-EGFR mAbs and EDA. Asterisks indicate the phagolysosome. The top rows show overlay of bright field and fluorescence, and the bottom rows show fluorescence only. Scale bar: 20 μm. (C) Percentage of macrophages that have phagocytosed A431 cells in the presence of an isotype or anti-EGFR mAb with or without EDA. MF, macrophage; TC, tumor cell. (D) Quantification of tumor cell size. (E and F) Representative images of anti-EGFR mAb–opsonized A431 tumor cells that have been phagocytosed and degraded by (E) control macrophages or (F) EDA-treated macrophages. Scale bar: 14 μm.