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

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

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

“…On these premises, several macrophages depleting/reprogramming therapies are under active investigation. The IKZF1-IRF4/IRF5 axis is necessary to drive the pro-tumoral polarization of macrophages, and its targeting exerted by IMiDs demonstrated the recovery of an anti-tumor functional status [44]. This event could contribute to the brilliant clinical results achieved by the combination of IMiDs with myeloma targeting monoclonal antibodies such as daratumumab and isatuximab, whose activity relies in part on the presence of functional macrophages [11,45,46].…”

Nanoengineered DNA origami with repurposed TOP1 inhibitors targeting myeloid cells for the mitigation of neuroinflammation

“…The copyright holder for this preprint this version posted October 4, 2021. ; https://doi.org/10.1101/2021.10.04.462880 doi: bioRxiv preprint iNOS expression in macrophages, and loss of Ikaros may promote repolarization to proinflammatory macrophages (51,52). Therefore, the role of Ikaros in macrophages and microglia is controversial and not fully understood.…”

A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment

“…For example, lenalidomide that was recently approved for patients with multiple myeloma [252] recruits the E3 ligase cereblon to target the Ikaros transcription factor (IKZF1). However, it has been recently observed that IKZF1 plays a pivotal role in promoting macrophages' skew towards a pro-tumour phenotype, and lenalidomide interrupts this switch, supporting their repolarisation towards a tumouricidal one [253]. New "degraders" that can target tumour cells and support myeloid cell "re-education" are enlisted in this development pipeline.…”