High FcγR expression on intratumoral macrophages enhances tumor-targeting antibody therapy

Hreinn Benonisson, Heng Sheng Sow, Cor Breukel, Jill Claassens, Conny Brouwers, Margot M. Linssen, Marieke F. Fransen, Marjolein Sluijter, Ferry Ossendorp, Thorbald van Hall, J. Sjef Verbeek

Research output: Contribution to journalArticleAcademicpeer-review

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. The Journ Al of Immunology, 2018, 201: 3741-3749.
Original languageEnglish
Pages (from-to)3741-3749
JournalJournal of Immunology
Volume201
Issue number12
DOIs
Publication statusPublished - 2018
Externally publishedYes

Cite this

Benonisson, H., Sow, H. S., Breukel, C., Claassens, J., Brouwers, C., Linssen, M. M., ... Verbeek, J. S. (2018). High FcγR expression on intratumoral macrophages enhances tumor-targeting antibody therapy. Journal of Immunology, 201(12), 3741-3749. https://doi.org/10.1016/j.ccell.2015.08.004