Journal
CELL REPORTS
Volume 35, Issue 1, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.108948
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Funding
- NIH [CA193815]
- Novita Pharmaceuticals
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The discovery of fascin inhibitor NP-G2-044 not only limits tumor metastasis but also reinvigorates anti-tumor immune responses in the tumor microenvironment, potentially increasing overall survival for late-stage cancer patients.
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.
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