Macrophages eliminate circulating tumor cells after monoclonal antibody therapy
Nuray Gül, … , Paul Kubes, Marjolein van Egmond
Nuray Gül, … , Paul Kubes, Marjolein van Egmond
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 3

ROS or RNS are not required for ADPh.

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ROS or RNS are not required for ADPh. (A and B) Formation of ROS after A...
(A and B) Formation of ROS after ADPh of opsonized tumor cells by Kupffer cells in livers of mice treated with (A) TA99 or (B) TA99, EDA, and L-NMMA. Scale bar: 25 μm. (C) Percentage of tumor cells interacting with Kupffer cells and (D) percentage phagocytosis of tumor cells by Kupffer cells in the livers of mice that were treated with TA99, TA99 and EDA, TA99 and L-NMMA, or TA99, EDA, and L-NMMA. (E) ROS production by macrophages after stimulation with 50 μg/ml peptidoglycan with and without EDA. Gates in the top right corners indicate ROS-producing macrophages. (F) Macrophages were incubated for 1 or 4 hours with B16F10-DiB cells and TA99 in the absence or presence of EDA. Macrophages were stained with F4/80-PE. Yellow circles denote double-positive cells (indicative of phagocytosis); red circles denote F4/80-PE+ macrophages; and blue circles denote nonphagocytosed B16F10-DiB cells. Numbers indicate percentage of total cells. (G–J) Phagocytosis of DiB-labeled (blue) B16F10gp75 cells by (G and H) LysoID-labeled (red) or (I and J) DiI-labeled (red) macrophages in the presence of (G and I) TA99 or (H and J) TA99 and EDA. Asterisks in G and H indicate the phagolysosome. Time points are indicated (minutes). The top rows show overlay of bright field and fluorescence, and the bottom rows show fluorescence only. Scale bar: 10 μm.