表皮生长因子受体（EGFR）突变型非小细胞肺癌（NSCLC）可能通过获得对表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）治疗的耐药性，使肿瘤微环境（TME）从非炎症状态重塑为炎症状态。
EGFR-mutant NSCLC may remodel TME from non-inflamed to inflamed through acquiring resistance to EGFR-TKI treatment.
机构信息
Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20030, China; Department of Postdoctoral Centre, Amoy Diagnostics, Xiamen, China.
Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 20030, China.
出版信息
Lung Cancer. 2024 Jun;192:107815. doi: 10.1016/j.lungcan.2024.107815. Epub 2024 May 10.
BACKGROUND
EGFR-TKI represent the standard first-line therapy for advanced NSCLC harboring EGFR mutations. However, resistance to EGFR-TKI inevitably develops in nearly all patients. Previous clinical study have demonstrated that, some patients that failed EGFR-TKI therapy show a benefit outcome from immunotherapy. Our objective is to explore the immune microenviroment remodeling induced by EGFR-TKI treatment in EGFR mutant lung cancer patients and to investigate the immune cell types and potential molecular signatures involved.
METHODS
A cohort of 37 EGFR mutant advanced-stage NSCLC patients, who are resistant to at least one type of TKI treatment, was retrospectively established. Both pre-treatment and TKI resistance tumor FFPE samples of each pairs were collected. Transcriptional profiling and bioinformatics analysis were employed to evaluate the change of immune associated hallmarks before and after EGFR-TKI therapy.
RESULTS
Tumor samples after EGFR-TKI treatment displayed enrichment of proinflammatory signaling like interferon-γ, allograft rejection and inflammatory response. Of note, cytotoxic factor granzyme A as well as PD-L1 were found to be more expressed in EGFR-TKI resistance samples. Approximately 33.3 % (11/33) of EGFR-TKI treated samples were classified as "hot" tumor, especially for EGFR L858R mutated NSCLC patients (46.7 %,7/15). Effector cells were significantly overexpressed in 'hot' tumors feature following TKI resistance. In addition, we found that four effector genes (CD8A, CDB8, GZMB, GZMK) showed higher expression in 'hot' tumors post-TKI resistance, and its 4-gene effector cell signature was found to have a good correlation with survival benefit in external immunotherapy database.
CONCLUSIONS
TKI treatment may initiate immune activation in EGFR mutant NSCLC, leading to changes in immune cell infiltration following TKI resistance. We mechanistically explored that this might be due to an increased immune response caused by the rise in effector cells post-TKI resistance.
背景
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）是 EGFR 突变型晚期 NSCLC 的标准一线治疗药物。然而，几乎所有患者最终都会对 EGFR-TKI 产生耐药。先前的临床研究表明，一些 EGFR-TKI 治疗失败的患者从免疫治疗中获益。本研究旨在探索 EGFR-TKI 治疗在 EGFR 突变型肺癌患者中诱导的免疫微环境重塑，并研究涉及的免疫细胞类型和潜在分子特征。
方法
回顾性收集了 37 例 EGFR 突变的晚期 NSCLC 患者的队列，这些患者对至少一种 TKI 治疗耐药。每对患者均采集了治疗前和 TKI 耐药肿瘤 FFPE 样本。采用转录组谱分析和生物信息学分析方法评估 EGFR-TKI 治疗前后免疫相关特征的变化。
结果
EGFR-TKI 治疗后的肿瘤样本显示促炎信号（如干扰素-γ、同种异体移植排斥和炎症反应）富集。值得注意的是，在 EGFR-TKI 耐药样本中发现细胞毒性因子 granzyme A 和 PD-L1 的表达增加。大约 33.3%（11/33）的 EGFR-TKI 治疗样本被归类为“热”肿瘤，尤其是 EGFR L858R 突变型 NSCLC 患者（46.7%，7/15）。TKI 耐药后，“热”肿瘤的效应细胞显著过表达。此外，我们发现，在 TKI 耐药后“热”肿瘤中，四个效应基因（CD8A、CDB8、GZMB、GZMK）表达较高，其 4 基因效应细胞特征与外部免疫治疗数据库中的生存获益具有良好的相关性。
结论
TKI 治疗可能在 EGFR 突变型 NSCLC 中引发免疫激活，导致 TKI 耐药后免疫细胞浸润发生变化。我们从机制上探讨了这可能是由于 TKI 耐药后效应细胞增加引起的免疫反应增强所致。
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