Plasminogen activator inhibitor-1 increases migration of monocytes to the tumor and skews their differentiation towards M2 macrophage phenotype (TUM6P.1002)

Abstract

Abstract Macrophages exhibiting M2 (pro-tumorigenic) phenotype have been linked to cancer progression. Plasminogen activator inhibitor-1 (PAI-1) is overexpressed by a variety of tumors and indicates poor clinical outcome. This pro-tumorigenic role has been linked to pro-angiogenic and anti-apoptotic functions. Here we demonstrate that PAI-1 is an orchestrator of monocyte migration towards tumor cells and of their M2 polarization. We observed that PAI-1 KO mice xenotransplanted with HT1080 PAI-1 KD cells exhibited tumors less infiltrated with macrophages compared to WT mice (p-value: 1.27E-09). In vitro, recombinant PAI-1 (40 nM) increased monocyte migration by an average 4-fold and increased the expression of CD163 (a M2 marker) by 10-fold (Median Fluorescence Intensity 3 to 30). PAI-1 induced monocyte production of IL-6 and IL-10 to 4000 pg/mL and 600 pg/mL, respectively, and activated STAT3 in the cells. Supporting the critical role for IL-6 and STAT3 in PAI-1 effect on M2 polarization in monocytes, we show that both blocking the IL-6 receptor (tocilizumab) and STAT3 activation (ruxolitinib) in monocytes treated with PAI-1 blocked CD163 expression. Our data point to a potential new pro-tumorigenic activity of PAI-1 via an effect on monocyte migration and polarization.