Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
Department of Microbiology and Immunology, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
Cell Rep. 2021 Apr 6;35(1):108948. doi: 10.1016/j.celrep.2021.108948.
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 蛋白是微丝束状伪足和侵袭伪足中的主要肌动蛋白结合蛋白，对于肿瘤细胞的迁移、侵袭和转移至关重要。小分子 Fascin 抑制剂可阻断肿瘤侵袭和转移，并提高荷瘤小鼠的总生存率。在这里，我们报告了一个发现，即 Fascin 阻断剂 NP-G2-044 还可以增强各种癌症的同源小鼠模型中的抗肿瘤免疫反应。Fascin 蛋白水平在肿瘤微环境中的常规树突状细胞（cDCs）中增加。从机制上讲，Fascin 抑制剂 NP-G2-044 增加了肿瘤内激活的 cDCs 的数量，并增强了 cDCs 的抗原摄取。此外，NP-G2-044 与 PD-1 阻断抗体联合使用，可显著增加 otherwise anti-PD-1 耐药肿瘤中活化的 CD8 T 细胞的数量。cDCs 中 Fascin 水平的降低，但不是肿瘤细胞中 Fascin 基因敲除，模拟了 NP-G2-044 的抗肿瘤免疫作用。这些数据表明，Fascin 抑制剂 NP-G2-044 可同时限制肿瘤转移并增强抗肿瘤免疫反应。
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