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

Yufeng Wang1, Mei Song2, Ming Liu3

  • 1Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.

Cell Reports
|April 7, 2021
PubMed

Insights

Small-molecule fascin inhibitors block tumor metastasis and also boost anti-tumor immune responses. Fascin blockade in dendritic cells (cDCs) enhances T-cell activation, offering a dual therapeutic approach for cancer.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Fascin is a key actin-bundling protein regulating tumor cell migration, invasion, and metastasis.
  • Fascin inhibitors have shown promise in blocking tumor spread and improving survival.
  • Elevated fascin expression is observed in tumor-associated dendritic cells (cDCs).

Purpose of the Study:

  • To investigate the impact of fascin inhibition on anti-tumor immune responses.
  • To elucidate the mechanisms by which fascin blockade affects immune cells within the tumor microenvironment.
  • To evaluate the combination therapy of fascin inhibition with PD-1 blockade.

Main Methods:

  • Utilized syngeneic mouse models of various cancers.
  • Administered fascin inhibitor NP-G2-044 and/or PD-1 blocking antibody.
  • Assessed immune cell populations (cDCs, CD8+ T cells) and function (antigen uptake) via flow cytometry and other analyses.
  • Manipulated fascin levels in cDCs and tumor cells to determine cell-type specificity.

Main Results:

  • Fascin inhibitor NP-G2-044 increased intratumoral activated cDCs and enhanced their antigen uptake.
  • Combined NP-G2-044 and PD-1 blockade significantly increased activated CD8+ T cells in refractory tumors.
  • Reducing fascin in cDCs, but not tumor cells, mimicked the anti-tumor immune effects of NP-G2-044.

Conclusions:

  • Fascin inhibition with NP-G2-044 demonstrates a dual action: inhibiting tumor metastasis and reinvigorating anti-tumor immunity.
  • Targeting fascin in cDCs is a viable strategy to enhance anti-tumor immune responses.
  • Fascin inhibitors represent a promising therapeutic avenue for combined cancer treatment strategies.
Keywords:
FascinIL-12anti-PD-1antigen uptakecancer immunotherapydendritic cellsfascin inhibitorsimmune checkpoint inhibitorinterferon gammatertiary lymphoid structure

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