CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
JNK 敲低增强 CAR-T 细胞细胞毒性
英文原题：JNK knockdown enhances CAR-T cell cytotoxicity.
查看英文原题
JNK knockdown enhances CAR-T cell cytotoxicity.
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研究概要
JNK 信号通路是 CAR-T 细胞杀伤功能的重要调控因子，为在人类肿瘤治疗中直接增强 CAR-T 疗效提供了潜在策略。
中文摘要
背景
提高 CAR-T 治疗实体瘤的效果可使癌症患者显著获益。鉴于活化 T 细胞核因子（NFAT）对 T 细胞功能至关重要，研究者假设，通过靶向 c-Jun N 端激酶（JNK）策略性调节 NFAT 活性，可增强 CAR-T 清除肿瘤的能力。
方法
研究者开发慢病毒编码的短发夹 RNA（shRNA），以稳定敲低 CAR-T 细胞中的 JNK。使用人外周血制备靶向人表皮生长因子受体 2（HER2）的 CAR-T，并在体外及两种人卵巢癌异种移植模型中评估功能。
结果
在 CAR-T 中敲低 JNK 会抑制抗原诱导的刺激和辅助性 T 细胞细胞因子产生，但增强体外及卵巢癌异种移植实验中的抗肿瘤细胞毒性。机制上，JNK 敲低导致颗粒酶 B 表达升高；过表达 NFATc1 可重现这一现象，提示其作用机制依赖 NFATc1。
结论
JNK 信号是 CAR-T 细胞毒性的关键调节因素，为直接增强人类癌症 CAR-T 疗效提供了潜在策略。
展开英文摘要原文
BACKGROUND
Boosting the performance of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors may provide a substantial advantage for cancer patients. Recognizing the vital role of the nuclear factor of activated T cells (NFAT) in T cell function, we hypothesized that the strategic regulation of NFAT activity by targeting c-Jun N-terminal Kinases (JNK) can bolster the tumor-eradicating potential of CAR-T cells.
METHODS
We developed a lentivirally encoded short-hairpin RNA (shRNA) for stable knockdown of JNK in CAR-T cells. CAR-T cells targeting human epidermal growth factor receptor 2 (HER2) were produced from human peripheral blood. Functionality was tested in vitro and in two xenograft models of human ovarian cancer.
RESULTS
JNK knockdown in CAR-T cells suppressed antigen-induced stimulation and helper T cell cytokine production, while enhancing anti-tumor cytotoxicity in vitro and in ovarian cancer xenograft experiments. Mechanistically, JNK knockdown led to elevated levels of granzyme B expression which could be recapitulated through overexpression of NFATc1, suggesting an NFATc1 dependent mechanism of action.
CONCLUSIONS
JNK signaling is a significant regulator of CAR-T cell cytotoxicity, offering a potential strategy to directly enhance CAR-T effectiveness in human cancer therapies.
论文信息
- 作者
- Kuhlmann CJ、Jepson CE、Blucas MT、Suleiman F、Manda A、Kamata YN、Kamata M
- 文献类型
- 预印本
- 期刊
- bioRxiv : the preprint server for biology2025 Aug 15
- 原文标识
- PubMed 40832339 · DOI 10.1101/2025.08.14.666406