Fascin inhibitor increases intratumoral dendritic cell activation and anti-cancer immunity
Yufeng Wang,
Mei Song,
Ming Liu,
Guoan Zhang,
Xian Zhang,
Ming O. Li,
Xiaojing Ma,
J. Jillian Zhang,
Xin-Yun Huang
Affiliations
Yufeng Wang
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA
Mei Song
Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA
Ming Liu
Program in Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Guoan Zhang
Proteomics and Metabolomics Core Facility, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA
Xian Zhang
Program in Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Ming O. Li
Program in Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Xiaojing Ma
Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA
J. Jillian Zhang
Novita Pharmaceuticals, Inc., New York, NY 10065, USA
Xin-Yun Huang
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA; Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine of Cornell University, New York, NY 10065, USA; Corresponding author
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.
