Li Ye, Shi Xinying, Mao Beibei, Wang Lingxiong, Wu Lijia, Li Jie, Jiao Shunchang
Department of Radiotherapy, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China; Oncology Laboratory, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China; Medical School of Chinese PLA, Beijing 100853, China.
Genecast Biotechnology Co., Ltd, Wuxi 214104, China.
Lung Cancer. 2022 Apr;166:161-169. doi: 10.1016/j.lungcan.2022.01.007. Epub 2022 Jan 11.
The aim of this study was to illustrate the genomic mutational landscape, tumor mutation burden (TMB), PD-L1 expression, CD8 T cell infiltration and their prognostic value in resectable Lung large cell neuroendocrine carcinoma (LCNEC).
The tumor tissues and corresponding normal tissues of 37 LCNEC patients undergoing surgical resection were collected and determined by whole exome sequencing (WES). Subsequently, the tumor samples were stained with the antibodies of PD-L1 and CD8 via multiplex immunohistochemistry (Multi IHC) to evaluate PD-L1 expression and CD8 T cells infiltration in stroma and tumor regions. Univariate and multivariate analysis were applied to assess the association among genomic features, immune profiles, clinical data and prognosis of LCNEC patients.
The median TMB was 5.42 mutations per megabase. Mutations in Wnt (p = 0.049) and Hippo (p = 0.005) pathways were markedly associated with higher TMB value, mutations in p53 pathway were related with higher stromal PD-L1 expression (p = 0.041). LCNEC patients with KEAP1 mutation (p = 0.044) or without adjuvant radiochemotherapy (p = 0.023) had significantly shorter OS. Multivariate analysis showed that high stromal CD8 + T cells infiltration was an independent favorable factor for disease free survival (p = 0.030). The patient stratification of KEAP1 mutation status and stroma PD-L1 expression was independent prognostic factors for overall survival (p = 0.049).
The investigation of prognostic factor in resectable LCNEC may provide guidance for timely intervention and new therapy strategy for LCENC patients.
本研究旨在阐明可切除性肺大细胞神经内分泌癌（LCNEC）的基因组突变图谱、肿瘤突变负荷（TMB）、程序性死亡受体配体1（PD-L1）表达、CD8 + T细胞浸润及其预后价值。
收集37例接受手术切除的LCNEC患者的肿瘤组织及相应正常组织，采用全外显子测序（WES）进行检测。随后，通过多重免疫组化（Multi IHC）用PD-L1和CD8抗体对肿瘤样本进行染色，以评估基质和肿瘤区域的PD-L1表达及CD8 T细胞浸润情况。采用单因素和多因素分析评估LCNEC患者的基因组特征、免疫特征、临床数据与预后之间的关联。
TMB中位数为每兆碱基5.42个突变。Wnt（p = 0.049）和Hippo（p = 0.005）信号通路突变与较高的TMB值显著相关，p53信号通路突变与较高的基质PD-L1表达相关（p = 0.041）。KEAP1突变（p = 0.044）或未接受辅助放化疗（p = 0.023）的LCNEC患者总生存期明显缩短。多因素分析显示，高基质CD8 + T细胞浸润是无病生存期的独立有利因素（p = 0.030）。KEAP1突变状态和基质PD-L1表达的患者分层是总生存期的独立预后因素（p = 0.049）。
对可切除性LCNEC预后因素的研究可为LCNEC患者的及时干预和新治疗策略提供指导。
