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

TitleFascin inhibitor increases intratumoral dendritic cell activation and anti-cancer immunity.
Publication TypeJournal Article
Year of Publication2021
AuthorsWang Y, Song M, Liu M, Zhang G, Zhang X, Li MO, Ma X, J Zhang J, Huang X-Y
JournalCell Rep
Volume35
Issue1
Pagination108948
Date Published2021 Apr 06
ISSN2211-1247
KeywordsAnimals, Antibodies, Antigens, Carrier Proteins, CD8-Positive T-Lymphocytes, Dendritic Cells, Drug Synergism, Immune Checkpoint Inhibitors, Immunity, Interferon-gamma, Interleukin-12, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Microfilament Proteins, Neoplasms, Programmed Cell Death 1 Receptor, Survival Analysis
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.

DOI10.1016/j.celrep.2021.108948
Alternate JournalCell Rep
PubMed ID33826900
PubMed Central IDPMC8050791
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 CA193815 / CA / NCI NIH HHS / United States

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