Niu Yuchun, Lin Anqi, Luo Peng, Zhu Weiliang, Wei Ting, Tang Ruixiang, Guo Linlang, Zhang Jian
Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Front Pharmacol. 2020 Aug 12;11:1213. doi: 10.3389/fphar.2020.01213. eCollection 2020.
Immune checkpoint inhibitors (ICIs) are an important treatment modality that must be considered for patients with lung adenocarcinoma (LUAD). However, ICIs are effective only in some of these patients. Therefore, identifying biomarkers that accurately predict the prognosis of patients with LUAD treated with ICIs can help maximize their therapeutic benefits. This study aimed to identify a new potential predictor to better select and optimally benefit LUAD patients.
We first collected and analyzed a discovery immunotherapy cohort comprising clinical and mutation data for LUAD patients. Then, we evaluated whether the specific mutated genes can act as predictive biomarkers in this discovery immunotherapy cohort and further validated the findings in The Cancer Genome Atlas (TCGA) project LUAD cohort. Gene set enrichment analysis (GSEA) was used to explore possible alterations in DNA damage response (DDR) pathways within the gene mutation. Moreover, we analyzed whole-exome sequencing (WES) and drug sensitivity response data for LUAD cell lines in the Genomics of Drug Sensitivity in Cancer (GDSC) database.
Among the mutated genes screened from both the ICI treatment and TCGA-LUAD cohorts, NTRK3 mutation (mutant-type NTRK3, NTRK3-MT) was strongly associated with immunotherapy. First, significant differences in overall survival (OS) were observed between patients with NTRK3-MT and those with NTRK3-WT in the ICI treatment cohort but not in the non-ICI-treated TCGA-LUAD cohort. We then analyzed the association of NTRK3-MT with clinical characteristics and found the tumor mutation burden (TMB) to be significantly higher in both NTRK3-MT cohorts. However, significant differences in neoantigen levels and smoking history were found only for NTRK3-MT in the LUAD cohort from TCGA. Furthermore, some immune-related genes and immune cell-related genes were significantly upregulated in patients with NTRK3-MT compared to those with NTRK3-WT. In addition, NTRK3 mutation affected the deregulation of some signaling pathways and the DDR pathway.
Our findings suggest that NTRK3-MT can predict the prognosis of patients with LUAD treated by ICIs and that it may have clinical significance for immunotherapy.
免疫检查点抑制剂（ICIs）是肺腺癌（LUAD）患者必须考虑的重要治疗方式。然而，ICIs仅对部分此类患者有效。因此，识别能够准确预测接受ICIs治疗的LUAD患者预后的生物标志物，有助于使他们的治疗获益最大化。本研究旨在识别一种新的潜在预测指标，以更好地筛选LUAD患者并使其获得最佳治疗效果。
我们首先收集并分析了一个发现性免疫治疗队列，其中包含LUAD患者的临床和突变数据。然后，我们评估了特定的突变基因在这个发现性免疫治疗队列中是否可作为预测生物标志物，并在癌症基因组图谱（TCGA）项目的LUAD队列中进一步验证了这些发现。基因集富集分析（GSEA）用于探索基因突变中DNA损伤反应（DDR）途径的可能改变。此外，我们分析了癌症药物敏感性基因组学（GDSC）数据库中LUAD细胞系的全外显子测序（WES）和药物敏感性反应数据。
在从ICI治疗队列和TCGA-LUAD队列中筛选出的突变基因中，神经营养酪氨酸激酶受体3（NTRK3）突变（突变型NTRK3，NTRK3-MT）与免疫治疗密切相关。首先，在ICI治疗队列中，NTRK3-MT患者与NTRK3野生型（NTRK3-WT）患者的总生存期（OS）存在显著差异，但在未接受ICI治疗的TCGA-LUAD队列中未观察到这种差异。然后，我们分析了NTRK3-MT与临床特征的关联，发现两个NTRK3-MT队列中的肿瘤突变负荷（TMB）均显著更高。然而，仅在TCGA的LUAD队列中，NTRK3-MT的新抗原水平和吸烟史存在显著差异。此外，与NTRK3-WT患者相比，NTRK3-MT患者中一些免疫相关基因和免疫细胞相关基因显著上调。另外，NTRK3突变影响了一些信号通路和DDR途径的失调。
我们的研究结果表明，NTRK3-MT可以预测接受ICIs治疗的LUAD患者的预后，并且它可能对免疫治疗具有临床意义。
