How to Reprogram Myeloma-Associated Macrophages: Target IKZF1

Tumor-derived cues fuel a state of chronic inflammation and sustained hematopoiesis that drive myeloid-cell dysfunction, including in the bone marrow (BM). This myeloid deviation can support immune tolerance, angiogenesis, cancer stemness, cell proliferation, matrix remodeling, mesenchymal transition, and metastatic spreading (1). Multiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of monoclonal plasma cells in the BM. Similar to solid tumor–associated macrophages, MAMs can either restrict or promote tumor progression depending on whether various factors have polarized them to an M1- or M2-like phenotype, respectively (1).

The immunomodulatory drug (IMiD) lenalidomide is approved for treating MM. Lenalidomide and the related IMiDs pomalidomide and thalidomide exert antitumor effects in multiple ways, including acting directly on cancer cells and surrounding immune cells. These IMiDs target the cereblon component of the CRL4^CRBN E3 ubiquitin ligase complex. In myeloma cells, this causes degradation of Ikaros transcription factor 1 (IKZF1) and IKZF3, which control expression of interferon regulatory factor 4 (IRF4) and MYC, translating into a direct cytotoxic effect on the myeloma cells (2). New insights into the immunomodulatory mechanisms of action of these IMiDs are emerging. In this context, Mougiakakos and colleagues describe how IMiD-dependent degradation of IKZF1 in MAMs reshapes the immune microenvironment in MM (3).

Mougiakakos and colleagues start by showing that IMiD therapy is associated with macrophage reprogramming in MM patients. They observe reduced expression of M2-like markers and immune suppression genes, higher expression of M1-like stimulatory molecules, and skewing of IL10/IL12 cytokine production toward the latter. By analyzing publicly available transcriptomic data and performing their own protein and functional analysis on M1- and M2-polarized macrophages, the authors identify a bidirectional link between IKZF1 expression and M1/M2 polarization status. More precisely, they find M2 polarization is coupled with higher expression and nuclear localization of IKZF1, and M2-polarized macrophages skew toward the M1 phenotype when exposed to lenalidomide. The IMiD-dependent macrophage reprogramming functionally translates into heightened tumoricidal activity and supports the expansion of IFNγ- and IL17-positive T cells.

Molecularly, IMiDs are shown to cause chromatin remodeling by IKZF1 at specific loci. There is a shift toward high trimethylation of H3K4 and low trimethylation of H3K27, both of which are associated with gene transcription, in the IRF4 promoter, while a mirror trimethylation arrangement is present in the IRF5 promoter. This switch in the histone methylation pattern results in IRF4 downregulation and IRF5 upregulation, both in vitro and in vivo.

Mougiakakos and colleagues confirm the results they obtained with human samples and cells using mice in which CRBN has been humanized to make it susceptible to IMiDs. In these mice, but not in wild-type mice, which are IMiD-unresponsive controls, lenalidomide treatment decreases expression of IKZF1 and IRF4 and increases IRF5. More importantly, IMiD-dependent in vivo macrophage reprogramming results in higher tumoricidal effects, as assessed by antibody-dependent cell phagocytosis of MM and lymphoma cell lines in the presence of CD38-specific or CD20-specific mAbs, respectively. These results provide the molecular grounds for the clinical synergy that occurs between IMiDs and therapeutic antibodies.

The identification of IKZF1 as a tumoricidal and immunostimulating macrophage gatekeeper has translational implications. It is necessary, however, to study how pervasive and important this mechanism is for TAMs other than MAMs, if we are to harness the knowledge to develop therapeutic options aimed at skewing tumor-promoting macrophages toward an antitumor phenotype, rather than pursuing strategies to eliminate tumor-promoting macrophages, which have so far proven challenging and poorly effective. IKZF1 is a susceptibility gene in systemic lupus erythematosus (4), therefore, these results may have clinical implications that go beyond cancer to inflammatory diseases.

V. Bronte has been a consultant/advisory board member for Xios Therapeutics, Codiak BioSciences, IO Biotech ApS, and ITeos Therapeutics SA. No disclosures were reported by the other author.