Effect of mutant variants of the KRAS gene on PD-L1 expression and on the immune microenvironment and association with clinical outcome in lung adenocarcinoma patients
Effect of mutant variants of the KRAS gene on PD-L1 expression and on the immune microenvironment and association with clinical outcome in lung adenocarcinoma patients
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DOI：
10.1016/j.lungcan.2018.05.009
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发表时间：
2018-07-01
期刊：
影响因子：
5.3
通讯作者：
Ilie, Marius
中科院分区：
文献类型：
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作者：
Falk, Alexander T.;Yazbeck, Nathalie;Ilie, Marius
目的：抗PD-1/PD-L1抑制剂对KRAS基因突变的肺腺癌(LADC)的作用尚有争议。研究对象和方法：在219例携带野生型(WT)或突变KRAS基因的LADC中，我们用免疫组织化学和自动数字图像分析的方法对几种免疫标志物的密度进行了定量。结果：携带突变KRAS-G12V的肿瘤中PD-L1的表达显著高于其他肿瘤(P=0.044)，而突变的KRAS-G12D肿瘤中CD66b+细胞密度增加(P=0.001)。KRAS突变患者肿瘤细胞中PD-L1的高表达与总生存期的改善相关(p=0.012)，而在WT患者中无相关性(p=0.385)，而免疫细胞中PD-L1的高表达与KRAS-WT患者的低OS相关(p=0.025)，在KRAS突变患者中无差异。结论：KRAS突变状态可以异质性地影响LADC患者的免疫微环境和生存，提示在对免疫治疗患者进行分层治疗时，应考虑肿瘤表达的特异性突变KRAS突变。
Objectives: The effect of anti-PD-1/PD-L1 inhibitors on lung adenocarcinomas (LADCs) with KRAS mutations is debatable. We examined the association between specific mutant KRAS proteins and the immune infiltrates with the outcome of patients with LADCs.Patients and methods: In 219 LADCs harboring either wild-type (WT) or mutated KRAS gene, we quantified the density of several immune markers by immunohistochemistry followed by automated digital image analysis. Data were correlated to clinicopathological parameters and outcome of patients.Results: Tumors harboring mutant KRAS-G12 V had a significantly higher PD-L1 expression compared to other tumors (p = 0.044), while mutant KRAS-G12D tumors showed an increase in the density of CD66b + cells (p = 0.001). High PD-L1 expression in tumor cells was associated to improved overall survival (OS) in KRAS mutant patients (p = 0.012), but not in the WT population (p = 0.385), whereas increased PD-L1 expression in immune cells correlated to poor OS of KRAS-WT patients (p = 0.025), with no difference in patients with KRAS mutations.Conclusions: KRAS mutational status can affect the immune microenvironment and survival of LADC patients in a heterogeneous way, implying that specific mutant KRAS variants expressed by the tumor should be considered when stratifying patients for immunotherapy.