Department of Medical Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Zheng Min Road, Shanghai, 200433, China.
Department of Pathology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, China.
J Hematol Oncol. 2019 Jul 12;12(1):75. doi: 10.1186/s13045-019-0762-1.
To depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates.
Whole-exome sequencing was performed on 189 surgically resected LUSC. TMB was defined as the sum of nonsynonymous single nucleotide and indel variants. CD8 tumor-infiltrating lymphocyte (TIL) density and PD-L1 expression were evaluated by immunohistochemistry. Six immune infiltrates were estimated using an online database.
The median TMB was 9.43 mutations per megabase. Positive PD-L1 expression and CD8 TILs density were identified in 24.3% and 78.8%. PIK3CA amplification was associated with significantly higher TMB (P = 0.036). Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8 TIL density (P < 0.001, P = 0.005, respectively). Low TMB and high CD8 TIL density were independently associated with longer disease-free survival (DFS) while none of them could individually predict the overall survival (OS). Combination of TMB and PD-L1 expression or TMB and CD8 TIL density could stratify total populations into two groups with distinct prognosis. Classifying tumor-immune microenvironment based on PD-L1 expression and CD8 TIL density showed discrepant genomic alterations but similar TMB, clinical features, and OS. Notably, patients with different smoking status had distinct prognostic factors.
The combination of TMB, PD-L1 expression, immune infiltrates, and smoking status showed the feasibility to subgroup stratification in Chinese patients with early-stage LUSC, which might be helpful for future design of personalized immunotherapy trials in LUSC.
描绘中国早期肺鳞状细胞癌（LUSC）的基因组景观，并研究其与肿瘤突变负担（TMB）、PD-L1 表达和免疫浸润的相关性。
对 189 例手术切除的 LUSC 进行全外显子组测序。TMB 定义为非同义单核苷酸和插入缺失变异的总和。通过免疫组织化学评估 CD8 肿瘤浸润淋巴细胞（TIL）密度和 PD-L1 表达。使用在线数据库评估 6 种免疫浸润。
中位 TMB 为 9.43 个突变/兆碱基。24.3%的患者 PD-L1 表达阳性，78.8%的患者 CD8 TIL 密度阳性。PIK3CA 扩增与 TMB 显著升高相关（P=0.036）。频繁的基因改变对 PD-L1 表达没有影响，但 PIK3CA 扩增和 KEAP1 突变与 CD8 TIL 密度显著降低独立相关（P<0.001，P=0.005）。低 TMB 和高 CD8 TIL 密度与无病生存期（DFS）延长独立相关，而两者均不能单独预测总生存期（OS）。TMB 和 PD-L1 表达或 TMB 和 CD8 TIL 密度的组合可以将总人群分为两组，具有不同的预后。基于 PD-L1 表达和 CD8 TIL 密度对肿瘤免疫微环境进行分类显示出不同的基因组改变，但 TMB、临床特征和 OS 相似。值得注意的是，不同吸烟状态的患者有不同的预后因素。
TMB、PD-L1 表达、免疫浸润和吸烟状态的组合显示了对中国早期 LUSC 患者进行亚组分层的可行性，这可能有助于未来设计 LUSC 患者的个性化免疫治疗试验。
