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

Abstract

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.

Fascin Inhibitors Decrease Cell Migration and Adhesion While Increase Overall Survival of Mice Bearing Bladder Cancers

“…NP-G2-044 blocked the migration of all of these bladder cancer cells with IC 50 values from 9 to 13 μM ( Figure 1 A–E). The actual IC 50 values for free NP-G2-044 are 0.27–0.39 μM (in the presence of 10% of serum), given that NP-G2-044 has an ~99.7% mouse plasma protein binding [ 35 , 36 ]. Hence, fascin inhibitors can inhibit the migration of bladder carcinoma cells.…”

“…NP-G2-044 inhibited the adhesion of all five bladder cancer cell lines with IC 50 values of 7.8–9.4 μM ( Figure 3 ). Given the 99.7% plasma protein binding of NP-G2-044 (in the presence of 100% serum) [ 35 , 36 ], the corresponding IC 50 values for free NP-G2-044 are 0.23–0.28 μM (in the presence of 10% of serum). These data demonstrate that NP-G2-044 inhibits the cell adhesion of bladder cancer cells.…”

“…The combination treatment of NP-G2-044 + anti-PD-1 antibody led to a greater extension of median overall survival of tumor-bearing mice than the mice treated with the anti-PD-1 antibody alone. Recently, we have shown that NP-G2-044 could increase intra-tumoral dendritic cell activation, and thus, anti-cancer immunity [ 36 ]. Recently, effective anti-PD-1 treatment was shown to require intratumoral dendritic cells producing IL-12, which stimulates antitumor CD8 + T cell immunity [ 44 ].…”

Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells

“…Both Fscn1 inhibitors have been identified by screening of compound libraries for their activity to bind Fscn1 in order to block its F-actin cross-linking activity in a cell-free environment. However, only NP-G2-044 was further tested with regard to its inhibitory activity on tumor cell motility, and subsequently in tumor models [ 19 , 39 ]. We comparatively assessed the effects of these two structurally distinct inhibitors on DCs and T cells to delineate which effects were common and thereby most probably consequences of Fscn1 inhibition, as well as to which extent both inhibitors evoked distinct and thereby, most probably, Fscn1 inhibition-independent, inhibitor-specific, off-target effects.…”

Circulating Fascin 1 as a Promising Prognostic Marker in Adrenocortical Cancer

“…Although this protein can also be expressed in normal tissues, recent studies have shown that FSCN1 is up-regulated in many types of metastatic tumors, and its expression correlates with enhanced aggressiveness, poor prognosis, and reduced survival ( 4 , 5 , 7 , 16 ). Selective block of FSCN1 in the tumor has been recently described to inhibit the metastatic process and stimulate anti-tumor immune responses in several mouse models of solid tumors ( 17 ).…”