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
英文原题:Machine learning developed a CD8(+) exhausted T cells signature for predicting prognosis, immune infiltration and drug sensitivity in ovarian cancer.
Machine learning developed a CD8(+) exhausted T cells signature for predicting prognosis, immune infiltration and drug sensitivity in ovarian cancer.
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CD8+耗竭T细胞(CD8+T ex)在癌症的进展和治疗反应中起着至关重要的作用。然而,很少有研究完全阐明CD8+T ex相关基因在卵巢癌(OC)中的特征。利用TCGA、GSE14764、GSE26193、GSE26712、GSE63885和GSE140082数据集,采用包含10种方法的综合机器学习流程构建了CD8+T ex相关预后特征(TRPS)。使用多个免疫治疗获益指标,包括肿瘤免疫功能障碍与排斥(TIDE)评分、免疫表型评分(IPS)、TMB评分和肿瘤逃逸评分,来探索TRPS在预测OC免疫治疗获益方面的表现。通过Enet(alpha=0.3)方法构建的TRPS是OC的独立危险因素,在预测患者临床结局方面表现出稳定而强大的性能。TRPS的C-index高于肿瘤分级、临床分期以及许多已开发的预后特征。低TRPS评分表明CD8+T细胞、B细胞、巨噬细胞M1和NK细胞水平较高,代表OC中相对免疫激活的生态系统。低风险评分的OC患者具有更高的PD1&CTLA4免疫表型评分、更高的TMB评分、更低的TIDE评分和更低的肿瘤逃逸评分,提示更好的免疫治疗反应。
此外,较高的TRPS评分表明癌症相关标志物评分较高,包括血管生成、EMT、缺氧、糖酵解和notch信号通路。体外实验表明,ARL6IP5在OC组织中下调,并抑制肿瘤细胞增殖。
本研究构建了一种新的OC TRPS,可作为预测OC患者预后、免疫浸润和免疫治疗获益的指标。
CD8 + exhausted T cells (CD8 + T ex ) played a vital role in the progression and therapeutic response of cancer.
However, few studies have fully clarified the characters of CD8 + T ex related genes in ovarian cancer (OC). The CD8 + T ex related prognostic signature (TRPS) was constructed with integrative machine learning procedure including 10 methods using TCGA, GSE14764, GSE26193, GSE26712, GSE63885 and GSE140082 dataset. Several immunotherapy benefits indicators, including Tumor Immune Dysfunction and Exclusion (TIDE) score, immunophenoscore (IPS), TMB score and tumor escape score, were used to explore performance of TRPS in predicting immunotherapy benefits of OC. The TRPS constructed by Enet (alpha = 0.
3) method acted as an independent risk factor for OC and showed stable and powerful performance in predicting clinical outcome of patients. The C-index of the TRPS was higher than that of tumor grade, clinical stage, and many developed signatures.
Low TRPS score indicated a higher level of CD8 + T cell, B cell, macrophage M1, and NK cells, representing a relative immunoactivated ecosystem in OC. OC patients with low risk score had a higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score and lower tumor escape score, suggesting a better immunotherapy response.
Moreover, higher TRPS score indicated a higher score of cancer-related hallmarks, including angiogenesis, EMT, hypoxia, glycolysis, and notch signaling. Vitro experiment showed that ARL6IP5 was downregulated in OC tissues and inhibited tumor cell proliferation. The current study constructed a novel TRPS for OC, which could serve as an indicator for predicting the prognosis, immune infiltration and immunotherapy benefits for OC patients.
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