GLI3 Is Required for M2 Macrophage Polarization and M2-Mediated Waldenström Macroglobulinemia Growth and Survival

Waldenstrom macroglobulinemia (WM) is a non-Hodgkin B-cell lymphoma, characterized by bone marrow infiltration with plasma cells and lymphocytes. The tumor microenvironment (TME) plays an important role in mediating WM cell biology, but the effects of macrophages on WM biology remains unclear. Here, we investigated the effects of macrophages on WM growth and survival and identified a novel role for transcription factor GLI3 in macrophage polarization. We found that co-culture of M0 and M2 macrophages promoted WM cell growth and survival, and co-culture WM cells with M0 macrophages induced M2-like phenotypes. Interestingly, GLI3 expression was induced in M2 macrophages (not M1), leading us to perform analysis of macrophages from mice lacking Gli3 in myeloid cells (<i>M-Gli3^-/-</i> mice). A subset of differentially expressed genes implicated a role for GLI3 in macrophage polarization. Macrophages from <i>M-Gli3^-/-</i> mice did not induce WM cell proliferation and reduced survival compared to M2 macrophages from WT mice. In addition, in vitro polarization of M0 macrophages from <i>M-Gli3^-/-</i> was not able to induce M2 markers such as CD163, despite inducing iNos expression (M1 marker). Taken together, these results suggest a role for M2 macrophages in promoting WM cell growth and identify GLI3 as a modulator of macrophage polarization.