Identification of Clonal Neoantigens Derived From Driver Mutations in anEGFR-Mutated Lung Cancer Patient Benefitting From Anti-PD-1
Identification of Clonal Neoantigens Derived From Driver Mutations in anEGFR-Mutated Lung Cancer Patient Benefitting From Anti-PD-1
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受益于抗 PD-1 的 EGFR 突变肺癌患者中驱动突变衍生的克隆新抗原的鉴定
DOI：
10.3389/fimmu.2020.01366
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发表时间：
2020
影响因子：
7.3
通讯作者：
Li Liu
中科院分区：
文献类型：
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作者：
Di Wu;Yangyang Liu;Xiaoting Li;Yiying Liu;Qifan Yang;Yuting Liu;Jingjing Wu;Chen Tian;Yulan Zeng;Zhikun Zhao;Yajie Xiao;Feifei Gu;Kai Zhang;Yue Hu;Li Liu
表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）已被推荐作为携带EGFR突变的非小细胞肺癌（NSCLC）患者的一线治疗。然而，对EGFR-TKI的获得性耐药是不可避免的。尽管靶向程序性细胞死亡1（PD-1）/PD-配体（L）1轴的免疫检查点阻断剂（ICB）已在许多癌症类型中取得临床成功，但已证明抗PD-1/PD-L1阻断剂在EGFR突变NSCLC患者中的临床疗效低于无EGFR突变的患者。在这里，我们报告了一例携带EGFR驱动突变的晚期NSCLC患者，在获得对EGFR-TKI的耐药后，从抗PD-1阻断治疗中获益。我们用下一代测序（NGS）表征了患者的突变情况，并成功鉴定了对EGFR外显子19缺失、TP 53 A116 T和DEND 6 B R398 Q突变编码的克隆新抗原的特异性T细胞应答。我们的研究结果支持在具有高免疫原性的特异性克隆新抗原的背景下，免疫检查点阻断在对EGFR-TKI获得性耐药的NSCLC患者中的潜在应用。应探索针对这些新抗原的个性化免疫调节治疗，以改善EGFR突变NSCLC患者的临床结局。
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been recommended as the first-line therapy for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, acquired resistance to EGFR-TKIs is inevitable. Although immune checkpoint blockades (ICBs) targeting the programmed cell death 1 (PD-1)/PD-ligand (L)1 axis have achieved clinical success for many cancer types, the clinical efficacy of anti-PD-1/PD-L1 blockades in EGFR mutated NSCLC patients has been demonstrated to be lower than those without EGFR mutations. Here, we reported an advanced NSCLC patient with EGFR driver mutations benefitting from anti-PD-1 blockade therapy after acquiring resistance to EGFR-TKI. We characterized the mutational landscape of the patient with next-generation sequencing (NGS) and successfully identified specific T-cell responses to clonal neoantigens encoded by EGFR exon 19 deletion, TP53 A116T and DENND6B R398Q mutations. Our findings support the potential application of immune checkpoint blockades in NSCLC patients with acquired resistance to EGFR-TKIs in the context of specific clonal neoantigens with high immunogenicity. Personalized immunomodulatory therapy targeting these neoantigens should be explored for better clinical outcomes in EGFR mutated NSCLC patients.