S100A8作为非小细胞肺癌免疫检查点抑制剂治疗疗效预测指标的研究

S100A8 as a predictive marker for non-small cell lung cancer immune checkpoint inhibitor therapy

目的探讨S100A8作为非小细胞肺癌(NSCLC)免疫检查点抑制剂(ICIs)治疗疗效预测指标的可行性与潜在机制。方法采用在线数据库,分析NSCLC肿瘤组织和正常肺组织中S100A8 mRNA、蛋白的表达情况以及S100A8 mRNA水平与NSCLC患者生存情况的关系。采用生物信息学分析法分析S100A8与肿瘤组织中免疫抑制性细胞、免疫抑制性分子、缺氧和血管生成的相关性。采用Kaplan-Meier对数秩检验分析血浆S100A8水平与接受ICIs治疗的NSCLC患者无进展生存期(PFS)的关系。结果肿瘤组织中,S100A8 mRNA和蛋白水平均高于正常肺组织(P=0.006 1)。S100A8 mRNA水平升高提示NSCLC患者生存预后差(P<0.000 1)。S100A8 mRNA水平越高,髓源性免疫抑制细胞(MDSC)(P<0.000 1)、调节性T细胞(Treg)(P<0.000 1)、M2型巨噬细胞(P<0.000 1)浸润的越多,IL-10生成的越多(P<0.000 1)且缺氧(P<0.000 1)和血管生成(P=0.007 4)越严重。生存曲线显示血浆S100A8水平升高提示接受ICIs治疗的NSCLC患者无进展生存期受损(P<0.05),且S100A8是PFS的独立影响因素(P<0.05)。结论 S100A8升高提示NSCLC患者处于免疫抑制状态,且接受ICIs治疗时PFS减短,S100A8具有作为NSCLC患者ICIs治疗疗效预测指标的可能性。

ICIs therapy improves the survival of NSCLC patients but with limited benefit. Therefore,reliable markers are needed to predict patient response. Hence, we aimed to study whether S100 A8 can be a predictive marker for NSCLC ICIs therapy. First, online databases were used to analyze S100 A8 expression and its correlation with survival of NSCLC patients. Then the correlations of S100 A8 mRNA and suppressive cells, suppressive molecules and hypoxia as well as angiogenesis were analyzed by bioinformatics. Last, as to NSCLC ICIs data,Kaplan-Meier analysis was applied to reveal the relationship between S100 A8 and PFS. Results showed that S100 A8 was overexpressed in NSCLC tissues compared with normal lung tissues at both the mRNA and protein levels. And high expression of S100 A8 was associated with poor overall survival(OS). High expression of S100 A8 correlated with increased infiltration of myeloid-derived suppressor cell(MDSC), Treg, and M2 macrophages, more production of IL-10 and more severe hypoxia as well as angiogenesis states. What’s more, Kaplan-Meier survival curves showed that elevated S100 A8 plasma levels predicted poor PFS. And S100 A8 was independently correlated with PFS. In conclusion, high S100 A8 expression in NSCLC indicated a severe immunosuppressive state and predicted poor PFS in NSCLC patients treated with ICIs. S100 A8 has the potential to be a novel predictive marker for NSCLC ICIs therapy.