?-catenin inhibition in tumor microenvironment macrophages promotes immunogenicity

Abstract Melanoma cells activate Wnt/β-catenin signaling in the tumor microenvironment (TME) to promote tumor progression and suppress dendritic cell-mediated anti-tumor immunity. However, the role of β-catenin in macrophages and its effect on anti-tumor immunity is largely undefined. In this study, using XAV939, a tankyrase inhibitor encapsulated in nanoparticles, we explored whether targeting β-catenin in macrophages can promote immunogenicity in TME. Our data show that the co-culture of macrophages with melanoma cell supernatants or melanoma cells in the presence of XAV939 nanoparticles significantly promotes the expression of CD80 and CD86, and suppresses the expression of PD-L1 and CD206 compared to macrophages treated with control nanoparticles. Similarly, XAV939 nanoparticle treatment of macrophages in co-culture conditions resulted in significantly increased TNF-α and IL-6 and reduced IL-10 production by macrophages compared to control groups. Our data suggest that targeted inhibition of β-catenin in tumor associated macrophages could overcome tolerance and promote anti-tumor immunity.