The IKZF1–IRF4/IRF5 axis controls polarization of myeloma-associated macrophages

Mougiakakos D, Bach C, Böttcher M, Beier F, Röhner L, Stoll A, Rehli M, Gebhard C, Lischer C, Eberhardt M, Vera J, Büttner-Herold M, Bitterer K, Balzer H, Leffler M, Jitschin S, Hundemer M, Awwad MH, Busch M, Stenger S, Schütz C, Krönke J, Mackensen A, Bruns H, Völkl S (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Cancer Immunology Research Cancer Immunology Research

Book Volume: 9

Pages Range: 265-278

Journal Issue: 3

DOI: 10.1158/2326-6066.CIR-20-0555

Abstract

The bone marrow niche has a pivotal role in progression, survival, and drug resistance of multiple myeloma cells. Therefore, it is important to develop means for targeting the multiple myeloma bone marrow microenvironment. Myeloma-associated macrophages (MAM) in the bone marrow niche are M2 like. They provide nurturing signals to multiple myeloma cells and promote immune escape. Reprogramming M2-like macrophages toward a tumoricidal M1 phenotype represents an intriguing therapeutic strategy. This is especially interesting in view of the successful use of mAbs against multiple myeloma cells, as these therapies hold the potential to trigger macrophage-mediated phagocytosis and cytotoxicity. In this study, we observed that MAMs derived from patients treated with the immunomodulatory drug (IMiD) lenalidomide skewed phenotypically and functionally toward an M1 phenotype. Lenalidomide is known to exert its beneficial effects by modulating the CRBN-CRL4 E3 ligase to ubiquitinate and degrade the transcription factor IKAROS family zinc finger 1 (IKZF1). In M2-like MAMs, we observed enhanced IKZF1 levels that vanished through treatment with lenalidomide, yielding MAMs with a bioenergetic profile, T-cell stimulatory properties, and loss of tumor-promoting capabilities that resemble M1 cells. We also provide evidence that IMiDs interfere epigenetically, via degradation of IKZF1, with IFN regulatory factors 4 and 5, which in turn alters the balance of M1/M2 polarization. We validated our observations in vivo using the CrbnI391V mouse model that recapitulates the IMiD-triggered IKZF1 degradation. These data show a role for IKZF1 in macrophage polarization and can provide explanations for the clinical benefits observed when combining IMiDs with therapeutic antibodies. See related Spotlight on p. 254

Authors with CRIS profile

Dimitrios Mougiakakos Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie Christian Bach Department of Medicine 5 – Haematology and Oncology Martin Böttcher Department of Medicine 5 – Haematology and Oncology Andrej Stoll Department of Medicine 5 – Haematology and Oncology Christopher Lischer Department of Dermatology Martin Eberhardt Lehrstuhl für Biochemie und Molekulare Medizin Julio Vera González Professur für Tumorimmunologie (Schwerpunkt Systembiologie) Maike Büttner-Herold Department of Nephropathology Andreas Mackensen Lehrstuhl für Innere Medizin V Heiko Bruns Department of Medicine 5 – Haematology and Oncology Simon Völkl Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Universitätsklinikum Ulm DE Germany (DE) Universitätsklinikum Regensburg DE Germany (DE) Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen DE Germany (DE) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Paul Ehrlich Institute / Paul-Ehrlich-Institut – Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel (PEI) DE Germany (DE)

How to cite

APA:

Mougiakakos, D., Bach, C., Böttcher, M., Beier, F., Röhner, L., Stoll, A.,... Völkl, S. (2021). The IKZF1–IRF4/IRF5 axis controls polarization of myeloma-associated macrophages. Cancer Immunology Research, 9(3), 265-278. https://doi.org/10.1158/2326-6066.CIR-20-0555

MLA:

Mougiakakos, Dimitrios, et al. "The IKZF1–IRF4/IRF5 axis controls polarization of myeloma-associated macrophages." Cancer Immunology Research 9.3 (2021): 265-278.

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