肿瘤细胞治疗研究
英文原题：Ligand-Receptor-Based Novel TWEAK CAR-T Exhibits Potent Antitumor Activity Against Liver Cancer by Targeting FN14.
Ligand-Receptor-Based Novel TWEAK CAR-T Exhibits Potent Antitumor Activity Against Liver Cancer by Targeting FN14.
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肝癌是最常见的致死性恶性肿瘤，现有治疗的疗效有限。肿瘤坏死因子受体超家族成员12A（FN14）在肝癌细胞中高表达，可促进肿瘤细胞增殖、迁移、侵袭和血管生成，因此是肝癌的潜在治疗靶点。作为靶向治疗手段，CAR-T（CAR-T）细胞在实体瘤治疗中显示出潜力。本研究基于FN14唯一的天然配体——肿瘤坏死因子超家族成员12（TWEAK）的胞外结构域，设计了靶向FN14的CAR，并在体内外检测其对肿瘤细胞的细胞毒作用。结果显示，多种肝癌细胞系均高表达FN14。TWEAK-CAR-T 细胞可在体外特异且有效地杀伤这些细胞；在体内，该细胞显著抑制高T细胞浸润的SK-Hep1异种移植瘤生长。此外，TWEAK-CAR-T 对多种癌症类型的不同肿瘤细胞系也显示出强效且广谱的细胞毒活性。研究结果提示，TWEAK-CAR-T 细胞疗法可能是治疗肝癌的有效策略。
Liver cancer is the most frequent fatal malignancy, and existing treatments have limited efficacy. Tumor necrosis factor receptor superfamily member 12A (FN14) is highly expressed in liver cancer cells and promotes tumor cell proliferation, migration, invasion, and angiogenesis, suggesting that FN14 is a suitable therapeutic target for liver cancer. As a targeted therapy, chimeric antigen receptor T (CAR-T) cells have demonstrated potential for treating solid cancers.
We designed a CAR targeting FN14 based on the extracellular domain of tumor necrosis factor superfamily member 12 (TWEAK), the only natural ligand for FN14, and tested its cytotoxic effect on tumor cells in vitro and in vivo. The results show that multiple liver cancer cell lines exhibit high FN14 expression. TWEAK-CAR-T cells specifically and effectively kill these cells in vitro. TWEAK-CAR-T cells also significantly suppress the growth of SK-Hep1 xenografts with high T-cell infiltration in the tumor.
Moreover, potent and broad cytotoxicity of TWEAK-CAR-T was observed against diverse tumor cell lines from multiple cancer types.
Our findings indicated that TWEAK-CAR-T cell therapy may be an effective therapeutic strategy for liver cancer.
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