Mougiakakos, Dimitrios and Bach, Christian and Boettcher, Martin and Beier, Fabian and Roehner, Linda and Stoll, Andrej and Rehli, Michael and Gebhard, Claudia and Lischer, Christopher and Eberhardt, Martin and Vera, Julio and Buettner-Herold, Maike and Bitterer, Katrin and Balzer, Heidi and Leffler, Magdalena and Jitschin, Simon and Hundemer, Michael and Awwad, Mohamed H. S. and Busch, Martin and Stenger, Steffen and Voelkl, Simon and Schuetz, Christian and Kroenke, Jan and Mackensen, Andreas and Bruns, Heiko (2021) The IKZF1-IRF4/IRF5 Axis Controls Polarization of Myeloma-Associated Macrophages. CANCER IMMUNOLOGY RESEARCH, 9 (3). pp. 265-278. ISSN 2326-6066, 2326-6074
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR-ASSOCIATED MACROPHAGES; ANTITUMOR-ACTIVITY; POOR-PROGNOSIS; LENALIDOMIDE; PHAGOCYTOSIS; CELLS; LYMPHOMA; IKAROS; MICROENVIRONMENT; DEXAMETHASONE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 21 Sep 2022 14:16 |
| Last Modified: | 21 Sep 2022 14:16 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47883 |
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