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
细胞因子、TGF-β 信号通路抑制剂和 CDK7/12/13 激酶抑制剂存在下 NK-92 细胞的转录谱变化
英文原题：Transcriptional Profile Change of NK-92 Cells in Presence of Cytokines, TGFβ Signaling Pathway Inhibitor and CDK7/12/13 Kinase Inhibitor.
查看英文原题
Transcriptional Profile Change of NK-92 Cells in Presence of Cytokines, TGFβ Signaling Pathway Inhibitor and CDK7/12/13 Kinase Inhibitor.
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中文摘要
自然杀伤（NK）细胞是先天免疫系统的效应细胞。细胞因子微环境影响 NK 细胞功能。NK 细胞细胞毒性失调可表现为生殖障碍，也可见于肿瘤转化组织。
因此，寻找能够调节 NK 细胞活性的免疫疗法具有相关性。本研究旨在评估 TGF 信号通路抑制剂和细胞周期蛋白依赖性激酶（CDK）7/12/13 抑制剂对 NK-92 细胞系转录谱的影响。
本研究中使用了细胞因子 TGF 1、IL-12、IL-15、IL-18 和 TNF，以及 TGF 受体 1 型（TGF R1）抑制剂 LY3200882 和 CDK7/12/13 抑制剂 THZ1。细胞在抑制剂和细胞因子存在下依次培养，随后评估 NCR2、NCR3、AHR、NCAM1、B3GAT1、EOMES、GATA3、KLRC1、KLRC2、CCL5、IL10 和 TBX21 的基因表达。
我们观察到抑制剂对 NK 细胞的直接作用。LY3200882 增加了 KLRC1 和 B3GAT1 的表达，并降低了 NCAM1。THZ1 增加了 KLRC1、KLRC2、AHR 和 EOMES 的表达，同时降低了 IL-10 和 NCR2。IL-12、IL-15、IL-18 和 TNF 改变了一些表型和细胞毒性受体及转录因子的基因表达。TGF 1 增加了 KLRC1、NCAM1 和 B3GAT1 的表达。用 LY3200882 阻断 TGF 依赖性信号可消除 TGF 1 的作用。
我们评估了 NK-92 细胞膜上 CD56 的存在，并发现其在 LY3200882 存在下增加。LY3200882 处理后，在 TGF 1 和绒毛膜癌细胞系 JEG-3 存在下，NK 细胞膜上 CD56 受体的表达降低。在 TGF 1 存在下，用 THZ1 预处理 NK 细胞降低了 NCAM1、B3GAT1 和 EOMES 的表达。
因此，LY3200882 部分中和了 TGF 1 对 NK 细胞受体基因表达的影响。THZ1 处理后接着 TGF 1 处理，促进了具有 CD56dim NK 细胞特征的 NK 细胞转录谱。即使没有细胞因子处理，LY3200882 和 THZ1 也均影响 NK 细胞转录。应考虑合成抑制剂对 NK 细胞的独立影响，以及它们在肿瘤细胞存在时的影响。
展开英文摘要原文
Natural killer (NK) cells are effector cells of the innate immune system. The cytokine microenvironment influences NK cell function. Dysregulation of NK cell cytotoxicity can manifest in reproductive disorders and is also observed in tumor-transformed tissues. The search for immunotherapies capable of regulating NK cell activity is therefore relevant.
This study aimed to evaluate the effect of the TGF signaling pathway inhibitor and the cyclin-dependent kinase (CDK) 7/12/13 inhibitor on the transcriptional profile of NK-92 cell line. In the study, the cytokines TGF 1, IL-12, IL-15, IL-18, and TNF , and the TGF receptor type 1 (TGF R1) inhibitor LY3200882 and the CDK7/12/13 inhibitor THZ1 were used.
The cells were cultured sequentially in the presence of inhibitors and cytokines, followed by assessment of the gene expression of NCR2 , NCR3 , AHR , NCAM1 , B3GAT1 , EOMES , GATA3 , KLRC1 , KLRC2 , CCL5 , IL10 and TBX21.
We observed direct effects of the inhibitors on NK cells. LY3200882 increased the expression of KLRC1 and B3GAT1 , and reduced NCAM1 . THZ1 increased the expression of KLRC1 , KLRC2 , AHR and EOMES , while it reduced IL-10 and NCR2 . IL-12, IL-15, IL-18, and TNF modified the gene expression of some phenotypic and cytotoxic receptors and transcription factors. TGF 1 increased the expression of KLRC1 , NCAM1 , and B3GAT1 . Blocking TGF -dependent signaling with LY3200882 abolished TGF 1 effects.
We assessed CD56 presence on NK-92 cell membrane and found its increase in the presence of LY3200882. After LY3200882 treatment, in the presence of TGF 1 and choriocarcinoma cell line JEG-3, the expression of CD56 receptor on NK cell membrane decreased. Pretreating NK cells with THZ1 decreased the expression of NCAM1 , B3GAT1 , and EOMES in the presence of TGF 1.
Thus, LY3200882 partially neutralized TGF 1 effects on the expression of NK cell receptor genes. THZ1 followed by TGF 1 treatment promoted NK cell transcriptional profile characteristic for CD56dim NK cells. Both LY3200882 and THZ1 affected the NK cell transcription even without cytokine treatment. The independent effects of synthetic inhibitors on NK cells, as well as their influence in the presence of tumor cells, should be considered.
论文信息
- 作者
- Mikhailova V、Marko O、Mkrtchyan E、Sokolov D
- 单位
- Research Institute of Obstetrics, Gynecology and Reproductology Named After D.O. Ott, 199034 St. Petersburg, Russia.Russia
- 期刊
- International journal of molecular sciences2026 Apr 17
- 原文标识
- PubMed 42074237 · DOI 10.3390/ijms27083599
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