Data from The IKZF1–IRF4/IRF5 Axis Controls Polarization of Myeloma-Associated Macrophages

Abstract

<div>Abstract<p>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 <i>in vivo</i> using the Crbn<sup>I391V</sup> 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.</p><p><i>See related Spotlight on p. 254</i></p></div>

Role of the ubiquitin–proteasome system on macrophages in the tumor microenvironment

“…It was found that CRBN-CRL4 degrades IKZF1 through UPS, and IKAROS family zinc finger 1 (IKZF1) is a transcription factor that regulates macrophage chromatin, which positively regulates IRF4 and negatively regulates IRF5 (Mougiakakos et al, 2021;Oh et al, 2018). IRF4/IRF5 expression affects the polarization state of TAMs, with IRF4 playing a major role in the induction of M2-like polarization in macrophages and IRF5 being highly expressed in M1-like polarized macrophages and mediating efficient TH1 and TH17 responses (Krausgruber et al, 2011;Nam & Lim, 2016;Satoh et al, 2010).…”

“…Studies at this stage showed that the immunomodulatory drug IMiD regulates the IRF4/IRF5 axis by mediating CRBN-CRL4 degradation of IKZF1, which shifts TAMs from M2-like polarization to M1-like polarization (Mougiakakos et al, 2021). The development of drugs based on CRBN-CRL4 to reprogram TAMs is very promising.…”