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

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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
Issue number12
Publication statusPublished - 2018
Externally publishedYes

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