Wang et al. demonstrated that inhibition of fascin, an actin-binding protein, activated intratumoral DCs, which in turn activated CD8+ T cells to initiate an immune response. Fascin inhibitor synergized with anti-PD-L1 antibody to prolonge survival in several syngeneic solid tumor models in an IL-12- and INFγ-dependent manner. Fascin was highly expressed in intratumoral DCs and macrophages, and fascin inhibition in DCs, but not in tumor cells, was essential for its synergistic effect. Fascin inhibitor plus anti-PD-L1 antibody increased accumulation, activation, and antigen uptake of intratumoral DCs, and increased CD8+ T cell proliferation and activation.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA. (2) Department of Microbiology and Immunology, Weill Corn
Author Info: (1) Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA. (2) Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA. (3) Program in Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (4) Proteomics and Metabolomics Core Facility, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA. (5) 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. (6) Novita Pharmaceuticals, Inc., New York, NY 10065, USA. (7) 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. Electronic address: xyhuang@med.cornell.edu.
