pMMR/MSS型结肠癌免疫治疗效果及预后标志物研究

Novel biomarker for immunotherapy and prognostic in colon cancer with mismatch repair proficiency or microsatellite stability

目的旨在建立可预测MSS/pMMR结直肠癌患者免疫治疗效果的新型生物标志物并探索可以逆转其免疫抑制的治疗方案。方法从癌症基因组图谱(TCGA)数据库中纳入261例MSS/pMMR结肠癌患者。根据肿瘤组织的免疫浸润情况对纳入人群通过无监督聚类分组,用单因素Cox回归分析和LASSO-Cox分析对组间的差异表达基因进行筛选并构建预测模型,用外部队列进行验证。最后,利用癌症药物敏感性基因组学数据库(GDSC)和CMap数据库探索增敏免疫治疗的潜在方法。结果建立了包含20个基因的预测模型,根据肿瘤的基因表达特征计算风险分数,将纳入人群分成高风险和低风险组。20个基因的表达特征是影响预后的独立因素并可以很好地预测免疫治疗效果。药物基因组学分析显示5-羟色胺受体阻滞剂联合免疫治疗可以增强高风险组患者的治疗效果。结论在MSS/pMMR结肠癌中,20基因模型可预测生存和免疫治疗效果,是一个具有应用前景的生物标志物。

Objective This study aimed to establish a predictive signature for identifying candidates for immunotherapy in patients with pMMR/MSS and explore potential approaches to convert their immunosuppressive conditions.Methods A total of 261 colon cancer patients with pMMR/MSS from The Cancer Genome Atlas colon cancer(TCGA-COAD)dataset were dissected based on the immunecell infiltration profile using unsupervised clustering algorithm.The differentially expressed genes were employed to construct a predictive signature through univariate Cox regression and least absolute shrinkage and selection operator(LASSO)-Cox analyses.Another two independent cohorts were subjected to validation to assess the robustness of the signature.Then,comprehensive analyses of immune status as well as biological pathway and functional enrichment analyses were performed to unveil the underlying mechanisms behind the signature.Finally,the Genomics of Drug Sensitivity in Cancer(GDSC)and Connectivity Map(CMap)databases were used to explore the potential approaches to enhance the effect of immunotherapy.Results A 20-gene signature was constructed.Two risk subsets were categorized based on the risk scores calculated by tumor expression profiles of the 20 genes.Notably,the signature was an independent prognostic factor and exhibited a powerful capacity for survival and immunotherapy response prediction.Additionally,we observed a significant difference in immune-cell infiltration profile between the two risk groups.The functional enrichment analyses indicated significant enrichment of immune-related pathways and inflammatory processes in low-risk patients.Moreover,high-risk group exhibited higher IC50 values for certain chemotherapy drugs,such as cisplatin and 5-fluorouracil.Pharmacogenomics analysis illustrated that serotonin receptor antagonist combined with immunotherapy may convert the insensitivity of immunotherapy in high-risk patients.Conclusion The 20-gene signature is a promising biomarker to predict survival outcome and response to immunotherapy in colon cancer patients with pMMR/MSS.