UC San Diego

The tumor microenvironment (TME) has emerged as a key contributor to cancer progression in numerous solid tumors as well as blood cancers that evolve in the bone marrow (BM). Within the TME, tumor-associated macrophages (TAMs) play a significant role in cancer cell survival and progression and have been implicated in producing an immuno-suppressive TME by generating inflammatory mediators, growth factors, cytokines, chemokines, etc. In multiple myeloma (MM), a fatal plasma cell neoplasm, inflammatory and anti-viral pathways promote disease progression. Interferon regulatory factor 4 (IRF4) is a transcription factor that has previously been shown to promote MM progression through enhanced survival of malignant plasma cells. Under physiological conditions, IRF4 also regulates macrophage polarization, where its expression drives alternative activation of macrophages primarily to M2-like (anti-inflammatory) phenotypes. However, the extent to which IRF4 activation or direct inhibition governs the polarization status and pro-tumoral activity of macrophages in the MM microenvironment has not been fully elucidated. Here, we show that IRF4 activation in MM macrophage models correspond with a more M2-like phenotype and direct inhibition of IRF4 shifts the polarization status toward a more M1-like, anti-tumoral phenotype.