基于UHPLC-Q-Orbitrap HRMS的PD-1抑制剂治疗的晚期肺腺癌患者血清代谢组学研究

Serum metabolomic study of PD-1 inhibitors based on UHPLC-Q-Orbitrap HRMS in patients with advanced lung adenocarcinoma

目的:探索晚期肺腺癌患者化疗联合免疫治疗前后的差异代谢物及代谢通路,为评估预后寻找生物指标。方法:利用超高效液相色谱-四极杆-静电场轨道阱质谱(UHPLC-Q-Orbitrap HRMS)技术,对14例晚期肺腺癌患者在第1次使用化疗联合PD-1抑制剂治疗前3 d的血清以及治疗2周期后的血清进行代谢组学分析。通过对采集得到的图谱进行峰识别和匹配等相关处理,应用主成分和正交偏最小二乘法-判别分析对代谢组学的数据进行分析,筛选出重要变量性投影>1和P<0.05的差异代谢物,并筛选代谢通路。结果:治疗前后血清代谢物质有明显差异,治疗后患者血清代谢物中谷氨酰丝氨酸、脯氨酸、犬尿氨酸、脱氢抗坏血酸、N-硬脂酰鞘磷脂、5-羟基吲哚乙酸水平升高;色氨酸、亮氨酰脯氨酸、柠檬酸、硬脂酸、吲哚丙烯酸、丙酰肉碱、吲哚、3-甲基吲哚水平降低。色氨酸代谢通路是治疗前后的差异代谢通路。结论:犬尿氨酸/色氨酸比值可能作为评估PD-1抑制剂治疗的晚期肺腺癌患者预后的生物指标。

Aim:To explore the differential metabolites and metabolic pathways of patients with advanced lung adenocarcinoma before and after chemotherapy combined with immunotherapy,and to find biological indicators for prognosis assessment.Methods:The serum samples of 14 patients with advanced lung adenocarcinoma 3 days before the first treatment of chemotherapy combined with PD-1 inhibitor,and after 2 cycles of treatment were collected.UHPLC-Q-Orbitrap HRMS technology was used for metabolic analysis.By performing related processing such as peak identification and matching on the collected atlas,principal component and orthogonal partial least squares-discriminant analysis were used to analyze metabolomic data,screen out the differential metabolites with variable importance in the projection>1 and P<0.05,and screen metabolic pathways.Results:There were significant differences in metabolites before and after treatment.Levels of glutamylserine,proline,kynurenine,dehydroascorbic acid,N-stearoylsphingomywlin,and 5-hydroxyindole acetic acid in serum metabolites of patients treated with chemotherapy combined with PD-1 inhibitors elevated;levels of tryptophan,leucine-proline,citric acid,stearic acid,indole acrylic acid,propionyl carnitine,indole,and 3-methylindole decreased.Tryptophan metabolic pathway was a differential metabolic pathway before and after treatment.Conclusion:Kynurenine/tryptophan ratio may be used as a biological indicator to evaluate the prognosis of PD-1 inhibitors in patients with advanced lung adenocarcinoma.