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
IL6R/STAT-3 轴与 TIGIT 的联合阻断及其对 NK 细胞抗前列腺癌细胞功能活性的影响
英文原题：Combination Blockade of the IL6R/STAT-3 Axis with TIGIT and Its Impact on the Functional Activity of NK Cells against Prostate Cancer Cells.
查看英文原题
Combination Blockade of the IL6R/STAT-3 Axis with TIGIT and Its Impact on the Functional Activity of NK Cells against Prostate Cancer Cells.
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研究概要
我们的结果揭示，联合使用针对 IL6R/STAT-3 轴和 TIGIT 的抑制剂可增强 NK 细胞对去势抵抗性前列腺癌细胞的杀伤功能。
中文摘要
方法
研究分析了22Rv1、LNCaP和DU145细胞中的细胞因子、趋化因子和生长因子分泌，并评估这些细胞中的NK配体、IL6R、STAT-3和磷酸化STAT-3表达。在NK-92细胞中，研究评估Stattic（Stt）和托珠单抗（Tcz）对NK受体的影响。此外，还检测破坏IL6R/STAT-3通路并阻断TIGIT，是否能增强NK-92细胞对DU145细胞的细胞毒性。
结果
DU145大量分泌M-CSF、VEGF、IL-6、CXCL8和TGF-β。此外，前列腺癌细胞CD155表达随侵袭性和转移状态升高。Stt和Tcz可降低DU145细胞STAT-3磷酸化，继而使NK-92细胞NKp46表达升高、TIGIT表达降低。最后，研究观察到，在前列腺癌细胞中破坏IL6R/STAT-3轴并阻断NK-92上的TIGIT，可通过提高可溶性FasL、颗粒酶A、颗粒酶B和颗粒溶素，增强NK-92细胞对DU145细胞的细胞毒作用。
结论
研究结果显示，联合使用靶向IL6R/STAT-3轴和TIGIT的抑制剂，可增强NK细胞对去势抵抗性前列腺癌细胞的功能活性。
展开英文摘要原文
METHODS
We analyzed the secretion of cytokines, chemokines, and growth factors in 22Rv1, LNCaP, and DU145 cells. In these cells, we also evaluated the expression of NK ligands, IL6R, STAT-3, and phosporylated STAT-3. In NK-92 cells, we evaluated the effects of Stattic (Stt) and tocilizumab (Tcz) on NK receptors. In addition, we assessed if the disruption of the IL6R/STAT-3 pathway and blockade of TIGIT potentiated the cytotoxicity of NK-92 cells versus DU145 cells.
RESULTS
DU145 abundantly secretes M-CSF, VEGF, IL-6, CXCL8, and TGF- β . Furthermore, the expression of CD155 was found to increase in accordance with aggressiveness and metastatic status in the prostate cancer cells. Stt and Tcz induce a decrease in STAT-3 phosphorylation in the DU145 cells and, in turn, induce an increase of NKp46 and a decrease of TIGIT expression in NK-92 cells. Finally, the disruption of the IL6R/STAT-3 axis in prostate cancer cells and the blocking of TIGIT on NK-92 were observed to increase the cytotoxicity of NK-92 cells against DU145 cells through an increase in sFasL, granzyme A, granzyme B, and granulysin.
CONCLUSIONS
Our results reveal that the combined use of inhibitors directed against the IL6R/STAT-3 axis and TIGIT enhances the functional activity of NK cells against castration-resistant prostate cancer cells.
论文信息
- 作者
- González-Ochoa S、Tellez-Bañuelos MC、Méndez-Clemente AS、Bravo-Cuellar A、Hernández Flores G、Palafox-Mariscal LA、Haramati J、Pedraza-Brindis EJ
- 单位
- Instituto Mexicano del Seguro Social (IMSS), Centro de Investigación Biomédica de Occidente (CIBO), División de Inmunología, Guadalajara, 44340, Jalisco, Mexico.Mexico
- 期刊
- Journal of immunology research2022
- 原文标识
- PubMed 35465350 · DOI 10.1155/2022/1810804
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