Fascin inhibitor increases intratumoral dendritic cell activation and anti-cancer immunity

• Main Authors: Yufeng Wang, Mei Song, Ming Liu, Guoan Zhang, Xian Zhang, Ming O. Li, Xiaojing Ma, J. Jillian Zhang, Xin-Yun Huang
• Format: Article
• Language: English
• Published: Elsevier 2021-04-01
• Series: Cell Reports
• Subjects: Fascin; fascin inhibitors; cancer immunotherapy; dendritic cells; anti-PD-1; IL-12
• Online Access: http://www.sciencedirect.com/science/article/pii/S221112472100262X

Summary: Fascin protein is the main actin-bundling protein in filopodia and invadopodia, which are critical for tumor cell migration, invasion, and metastasis. Small-molecule fascin inhibitors block tumor invasion and metastasis and increase the overall survival of tumor-bearing mice. Here, we report a finding that fascin blockade additionally reinvigorates anti-tumor immune response in syngeneic mouse models of various cancers. Fascin protein levels are increased in conventional dendritic cells (cDCs) in the tumor microenvironment. Mechanistically, fascin inhibitor NP-G2-044 increases the number of intratumoral-activated cDCs and enhances the antigen uptake by cDCs. Furthermore, together with PD-1 blocking antibody, NP-G2-044 markedly increases the number of activated CD8+ T cells in the otherwise anti-PD-1 refractory tumors. Reduction of fascin levels in cDCs, but not fascin gene knockout in tumor cells, mimics the anti-tumor immune effect of NP-G2-044. These data demonstrate that fascin inhibitor NP-G2-044 simultaneously limits tumor metastasis and reinvigorates anti-tumor immune responses.