目标:越来越多的证据表明,风险分层之间存在密切的相关性,结肠腺癌(COAD)的预后和免疫环境。然而,不同COAD患者的免疫治疗效果不同。因此,目前的工作倾向于使用免疫相关基因来开发基因对模型来评估COAD的预后,并开发了一种新的COAD风险分层方法,有利于更好地预测患者的免疫治疗效果。
方法:具体来说,来自TCGA和GEO(GSE14333和GSE39582)数据库,我们首先收集了基因表达谱,COAD患者相关生存随访信息。通过系统的生物信息学分析,我们建立了三对“免疫基因对”的结肠癌预后相关模型,单、多变量和lassocox回归分析验证了模型的稳定性。大多数免疫细胞在模型计算的两个风险亚组之间显示出明显不同的浸润水平。更多,我们还进行了单细胞RNA-seq分析,以验证免疫基因对模型中选定的基因.
结果:建立了具有三对“免疫基因对”的结肠癌预后相关模型,并通过多个数据集进行了验证。对COAD免疫景观的分析表明,通过COAD预后相关模型获得的低风险亚组可以进一步分为三个具有不同预后的亚组。然后,我们应用肿瘤在线预后分析平台(ToPP)构建了使用这5个基因的预后模型.结果表明,APOD,ISG20和STC2是风险因素,而CXCL9和IL7R是保护因子。我们还发现,只有五基因模型也能预测COAD患者的预后,表明基因对模型的鲁棒性。在这五个基因中,包括CXCL9,APOD,STC2、ISG20和IL7R,在基因对模型中,单细胞RNA测序显示CXCL9和IL7R在炎性巨噬细胞中的高表达。利用细胞-细胞相互作用和轨迹分析,数据表明,CXCL9+/IL7R+促炎巨噬细胞比CXCL9-/IL7R-促炎巨噬细胞能够分泌和激活更多的抗肿瘤途径.
结论:简而言之,我们已经成功地开发了一个“免疫基因对”相关模型,该模型可以判断COAD患者的预后状态,并可能有助于风险分层和评估免疫治疗的潜在受益者,为抗COAD管理和治疗提供新思路。
OBJECTIVE: There is increasing evidence for a close correlation between risk stratification, prognosis and the immune environment in colon adenocarcinoma (COAD). However, the efficacy of immunotherapy is different among different patients with COAD. Therefore, the current work tends to use immune-related gene to develop a gene-pair model to evaluate the COAD prognosis, and to develop a new method for risk stratification of COAD, which is conducive to better predict the immunotherapy effect of patients.
METHODS: Specifically, from the TCGA and GEO (GSE14333 and GSE39582) databases, we first collected gene expression profiles, associated survival follow-up information of COAD patients. Through systematic bioinformatics analysis, we established a prognosis-related model of colon cancer with three pairs of \"immune gene pairs\", with uni- and multivariate and lasso cox regression analyses verifying the model stability. Most immune cells showed markedly different levels of infiltration between the two risk subgroups calculated by the model. More, single-cell RNA-seq analyses were also performed to validate the selected genes in the immune gene-pair model.
RESULTS: A prognosis-related model of colon cancer with three pairs of \"immune gene pairs\" were built and validated by several datasets. The analysis of immune landscape of COAD revealed that low-risk subgroup obtained by the prognosis-related model for COAD can be further divided into three subclusters with different prognosis. Then, we applied the Tumor online Prognostic analyses Platform (ToPP) to construct a prognostic model using these five genes. Results show that APOD, ISG20 and STC2 are risk factors, while CXCL9 and IL7R are protection factors. We also found that only the five-gene model could also predict the prognosis of COAD patients, indicating the robustness of the gene-pair model. Among the five genes, including CXCL9, APOD, STC2, ISG20, and IL7R, in the gene-pair model, single-cell RNA sequencing reveals the high expression of CXCL9 and IL7R in inflammatory macrophages. Using cell-cell interaction and trajectory analysis, data indicate that CXCL9+/IL7R+ pro-inflammatory macrophages were capable of secreting and activating more anti-tumor pathways than CXCL9-/IL7R- pro-inflammatory macrophages.
CONCLUSIONS: In short, we have successfully developed an \"immune gene pair\" related model that can judge the prognostic status of patients with COAD and may contribute to risk stratification and evaluate potential beneficiaries of immunotherapy, providing new ideas for the anti-COAD management and therapy.