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
一种用于改善膀胱癌预后和免疫治疗反应预测的新型 NK 细胞相关基因特征
英文原题：A Novel Natural Killer Cell-related Gene Signature for Improving the Prediction of Prognosis and Immunotherapy Response in Bladder Cancer.
查看英文原题
A Novel Natural Killer Cell-related Gene Signature for Improving the Prediction of Prognosis and Immunotherapy Response in Bladder Cancer.
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研究概要
我们的特征在预测预后和免疫治疗反应方面的能力是稳健的。希望这些结果能为 BLCA 研究和患者免疫治疗提供新的见解。
研究思路结论见上方概要
背景
膀胱癌（BLCA）是全球范围内常见的诊断癌症，具有高复发率和转移率。免疫疗法在膀胱癌的临床管理中日益受到认可。此外，在BLCA中开发自然杀伤（NK）细胞相关免疫疗法的前景广阔。
方法
我们建立并验证了基于NK细胞相关基因表达的预后特征。随后，我们计算了BLCA样本的NKscore，并将其与临床结局、BLCA分子亚型、肿瘤微环境（TME）以及免疫检查点抑制剂（ICI）和化疗药物的预测疗效相关联，以深入探究NKscore的意义。最后，通过实时定量PCR、CCK-8实验（CCK-8）、Transwell实验和集落形成实验验证了NK特征基因HECTD1在BLCA中的作用。
结果
我们分析了NK细胞相关基因，并鉴定出六个与预后显著相关的基因。高NK评分显著代表更差的预后。NKscore与BLCA的七种经典分子亚型分类显著相关。此外，NKscore与NK相关免疫检查点正相关，提示新兴的NK细胞免疫检查点抑制剂，如monalizumab，可能对高NKscore患者具有潜在的治疗前景。T细胞炎症评分（TIS）和肿瘤免疫功能障碍与排斥（TIDE）评分的结果证实了高NK评分患者适合免疫治疗。同样，高NK评分患者可能更适合几种重要的化疗药物。功能实验表明，敲低HECTD1显著减弱了肿瘤细胞的增殖、迁移和侵袭能力。
展开英文摘要原文
BACKGROUND
Bladder cancer (BLCA) is a commonly diagnosed cancer worldwide that exhibits high rates of recurrence and metastasis. Immunotherapy is increasingly being recognised in the clinical management of bladder cancer. In addition, the prospect of developing Natural Killer (NK) cell-related immunotherapy is promising in BLCA.
METHODS
We established and verified a prognostic signature based on NK cell-related gene expression. We then calculated the NKscore of BLCA samples and correlated it with the clinical outcomes, molecular subtypes of BLCA, tumour microenvironment (TME), and predicted efficacy of immune checkpoint inhibitors (ICI) and chemotherapy drugs to thoroughly explore the implications of the NKscore. Finally, the role of the NK signature gene HECTD1 in BLCA was verified by Quantitative Real-time PCR, Cell Counting Kit-8 Assay (CCK-8), Transwell Assay and Colony Formation Experiment.
RESULTS
We analysed NK cell-associated genes and identified six genes with significant prognostic relevance. A high NK score significantly represents a worse prognosis. NKscore was significantly correlated with seven types of classical molecular subtype classifications of BLCA. In addition, NKscore positively correlates with NK-related immune checkpoints, suggesting that emerging NK cell immune checkpoint inhibitors, such as monalizumab, may have potential therapeutic promise for patients with high NKscore. The results of the T cell inflamed score (TIS) and tumour immune dysfunction exclusion (TIDE) score confirmed the suitability of immunotherapy for patients with a high NK score. Likewise, patients with a high NK score may be more suitable for several significant chemotherapeutic drugs. Functional experiments showed that the knockdown of HECTD1 significantly attenuated the proliferation, migration, and invasion ability of tumour cells.
CONCLUSION
To sum up, the capability of our signature to predict prognosis and immunotherapy response was robust. Hopefully, these results will provide new insights for BLCA research and patient immunotherapy.
论文信息
- 作者
- Ma X、Wei X、Yang G、Li S、Liu R
- 单位
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Combinatorial chemistry & high throughput screening2024
- 原文标识
- PubMed 37653625 · DOI 10.2174/1386207326666230831164358