1. High FcγR Expression on Intratumoral Macrophages Enhances Tumor-Targeting Antibody Therapy
- Author
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Ferry Ossendorp, Jill W. C. Claassens, Conny Brouwers, Hreinn Benonisson, Heng Sheng Sow, Marjolein Sluijter, Margot M. Linssen, Thorbald van Hall, J. Sjef Verbeek, Marieke F. Fransen, and Cor Breukel
- Subjects
Male ,0301 basic medicine ,Immunology ,Melanoma, Experimental ,Clone (cell biology) ,Antibodies ,Mice ,03 medical and health sciences ,Immune system ,Antigen ,Antigens, Neoplasm ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Immunology and Allergy ,Receptor ,Melanoma ,Mice, Knockout ,Regulation of gene expression ,Tumor microenvironment ,Membrane Glycoproteins ,Chemistry ,Macrophages ,Receptors, IgG ,Toll-Like Receptors ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Killer Cells, Natural ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,Interleukin-2 ,Female ,Immunization ,Immunotherapy ,Oxidoreductases ,CD8 - Abstract
Therapy with tumor-specific Abs is common in the clinic but has limited success against solid malignancies. We aimed at improving the efficacy of this therapy by combining a tumor-specific Ab with immune-activating compounds. In this study, we demonstrate in the aggressive B16F10 mouse melanoma model that concomitant application of the anti-TRP1 Ab (clone TA99) with TLR3-7/8 or -9 ligands, and IL-2 strongly enhanced tumor control in a therapeutic setting. Depletion of NK cells, macrophages, or CD8+ T cells all mitigated the therapeutic response, showing a coordinated immune rejection by innate and adaptive immune cells. FcγRs were essential for the therapeutic effect, with a dominant role for FcγRI and a minor role for FcγRIII and FcγRIV. FcγR expression on NK cells and granulocytes was dispensable, indicating that other tumoricidal functions of NK cells were involved and implicating that FcγRI, -III, and -IV exerted their activity on macrophages. Indeed, F4/80+Ly-6C+ inflammatory macrophages in the tumor microenvironment displayed high levels of these receptors. Whereas administration of the anti-TRP1 Ab alone reduced the frequency of these macrophages, the combination with a TLR agonist retained these cells in the tumor microenvironment. Thus, the addition of innate stimulatory compounds, such as TLR ligands, to tumor-specific Ab therapy could greatly enhance its efficacy in solid cancers via optimal exploitation of FcγRs.
- Published
- 2018
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