RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
基于 IFN-γ 与 TNF-α 协同诱导 CXCL10 高表达构建自驱动抗 αFR CAR 工程化 NK 细胞
英文原题：Construction of self-driving anti-αFR CAR-engineered NK cells based on IFN-γ and TNF-α synergistically induced high expression of CXCL10.
查看英文原题
Construction of self-driving anti-αFR CAR-engineered NK cells based on IFN-γ and TNF-α synergistically induced high expression of CXCL10.
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研究概要
基于 IFN-γ 与 TNF-α 协同诱导 CXCL10 高表达的机制，构建共表达 CXCR3A 的第四代 NK-92-FR-CAR 细胞，体外可高效杀伤 FR 阳性卵巢癌细胞并分泌 IFN-γ、TNF-α，迁移能力优于对照。
中文摘要
目的
阐明 NK-92-FR-CAR 细胞杀伤卵巢癌细胞时诱导趋化因子 CXCL10 分泌的机制。研究者推测，NK-92-FR-CAR-CXCR3A 可靶向 FR 并对 CXCL10 产生趋化反应，因此可能具有更强的卵巢癌杀伤作用。
方法
研究 TNF-α 和 IFN-γ 联合刺激强烈诱导卵巢癌细胞表达 CXCL10 的机制。构建共表达 CXCR3A 和 FR-CAR 的第四代 NK-92-FR-CAR-CXCR3A 细胞，并在体外和体内评估其杀伤和迁移效应。
结果
RNA 测序首先显示，与 NK-92-FR-CAR 共培养的卵巢癌细胞中趋化因子 CXCL10 表达升幅最大。其次，细胞因子刺激实验证实，NK-92-FR-CAR 分泌的 IFN-γ 和 TNF-α 可协同诱导卵巢癌细胞高表达 CXCL10。进一步信号通路实验显示，IFN-γ 和 TNF-α 增强了 IFN-γ–IFNGR–JAK1/2–STAT1–CXCL10 信号轴的激活。细胞毒性实验显示，NK-92-FR-CAR-CXCR3A 细胞不仅能在体外高效杀伤 FR 阳性卵巢癌细胞，还能分泌 IFN-γ 和 TNF-α。Transwell 实验发现，NK-92-FR-CAR-CXCR3A 的迁移能力高于 NK-92-FR-CAR。该细胞在不同卵巢癌小鼠异种移植模型中有效杀伤肿瘤细胞，并增加其向肿瘤组织的浸润。
结论
本研究证实，FR-CAR 工程化 NK 细胞分泌的 IFN-γ 和 TNF-α 可协同诱导卵巢癌细胞高表达 CXCL10；研究还构建了基于 CXCL10 实现自驱动、突破迁移屏障的 FR-CAR 工程化 NK 细胞，有望为卵巢癌治疗提供新的手段。
展开英文摘要原文
OBJECTIVES
To elucidate the mechanism by which NK-92- FR-CAR cells induce the secretion of chemokine CXCL10 during killing ovarian cancer cells. It is speculated that NK-92- FR-CAR-CXCR3A can target FR and have chemotaxis of CXCL10, and they may have stronger killing effect of ovarian cancer.
METHODS
Study the mechanism of CXCL10 expression strongly induced by TNF- and IFN- combined stimulation in ovarian cancer cells. Construct the fourth generation of NK-92- FR-CAR-CXCR3A cells, which were co-expressed CXCR3A and FR-CAR. Evaluate the killing and migration effects of NK-92- FR-CAR-CXCR3A in vitro and in vivo.
RESULTS
RNA sequencing (RNA-seq) first revealed that the expression level of the chemokine CXCL10 was most significantly increased in ovarian cancer cells co-cultured with NK-92- FR-CAR. Secondly, cytokine stimulation experiments confirmed that IFN- and TNF- secreted by NK-92- FR-CAR synergistically induced high CXCL10 expression in ovarian cancer cells. Further signaling pathway experiments showed that IFN- and TNF- enhanced the activation level of the IFN- -IFNGR-JAK1/2-STAT1-CXCL10 signaling axis. Cytotoxicity experiments showed that NK-92- FR-CAR-CXCR3A cells could not only efficiently kill FR-positive ovarian cancer cells in vitro but also secrete IFN- and TNF- . Higher migration than that of NK-92- FR-CAR was detected in NK-92- FR-CAR-CXCR3A using transwell assay. NK-92- FR-CAR-CXCR3A effectively killed tumor cells in different mouse xenograft models of ovarian cancer and increased infiltration into tumor tissue.
CONCLUSION
This study confirmed that IFN- and TNF- secreted by FR-CAR-engineered NK cells can synergistically induce high expression of CXCL10 in ovarian cancer cells and constructed self-driving FR-CAR-engineered NK cells that can break through migration barriers based on CXCL10, which may provide a new therapeutic weapon for ovarian cancer.
论文信息
- 作者
- He M、Ao X、Yang Y、Xu Y、Liu T、Ao L、Guo W、Xing W
- 第一作者单位
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China; Department of Gynecology and Obstetrics, The 958th Hospital, Southwest Hospital, Army Medical University, Chongqing, China.China
- 通讯作者单位
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: yiping@cqmu.edu.cn.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Neoplasia (New York, N.Y.)2024 Dec
- 原文标识
- PubMed 39366148 · DOI 10.1016/j.neo.2024.101065
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