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| 中国肺鳞癌患者的精准免疫治疗“希望之路” | Journal of Hematology & Oncology |
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论文标题：Genomic landscape and its correlations with tumor mutational burden, PD-L1 expression, and immune cells infiltration in Chinese lung squamous cell carcinoma
期刊：Journal of Hematology & Oncology
作者：Tao Jiang, Jinpeng Shi, Zhengwei Dong, Likun Hou, Chao Zhao, Xuefei Li, Beibei Mao, Wei Zhu, Xianchao Guo, Henghui Zhang, Ji He, Xiaoxia Chen, Chunxia Su, Shengxiang Ren, Chunyan Wu & Caicun Zhou
发表时间：2019/07/12
DOI：10.1186/s13045-019-0762-1
微信链接：https://mp.weixin.qq.com/s/icMyVWFrdcTxFHF0nuLeCg
肺鳞癌是肺癌最常见的组织学类型之一。与肺腺癌不同的是，肺鳞癌患者的治疗策略在过去几十年中进展非常缓慢，导致此类患者的总体预后较差。近期，以免疫检查点抑制剂PD-1/PD-L1为靶点的免疫治疗，革新了晚期肺鳞癌的一线、二线及后线的治疗策略。然而，在临床实践中，研究者发现PD-1/PD-L1抗体单药治疗未加选择的晚期肺鳞癌患者，有效率仅20%左右，探索有效的疗效预测标志物与合理的联合免疫治疗策略是该领域亟待解决的关键问题。
近日，来自同济大学上海市肺科医院的研究人员在Journal of Hematology & Oncology 发表了题为 “Genomic landscape and its correlations with tumor mutational burden, PD-L1 expression and immune cells infiltration in Chinese lung squamous cell carcinoma” 的研究。
该研究通过回顾性搜集189例接受手术切除的肺鳞癌样本，进行深度全外显子组测序，计算每个样本的TMB（高TMB定义为大于总体的75%分位数）。CD8+ 肿瘤浸润淋巴细胞（TIL）和PD-L1的表达通过免疫组织化学染色（IHC）进行检测，阳性cutoff值均定义为>5%。研究结果如下：在纳入的合格样本中8个高频突变基因被发现，包括TP53, KMT2C, NFE2L2, KEAP1, CDKN2A, PTEN, FBXW7 和 PIK3CA。其中FGFR1和PIK3CA的扩增比率分别为19%和11%。除吸烟史外，基线特征资料与TMB表达无关。FGFR1, PIK3CA 或 SOX2的扩增与更高的TMB相关。PD-L1和CD8+ TIL阳性表达率分别为24.3%和78.8%。NFE2L2 突变和 PIK3CA扩增与更高的PD-L1表达相关。
图1.肺鳞癌基因图谱及其与PD-L1, CD8+ TIL和TMB间的关系
值得注意的是，TMB表达与PD-L1或CD8+ TIL阳性率均无相关性。TMB，CD8+ TIL和PD-L1表达单一指标均不能预测预后，但是TMB联合PD-L1或CD8+ TIL可以很好的预测预后。
图2. PD-L1, CD8+ TIL和TMB单独或联合预测肺鳞癌患者的DFS和OS
利用PD-L1和CD8+ TIL表达水平将肺鳞癌的免疫微环境分成经典的四型（TME type I-IV），结果发现：四种TME具有相似的TMB水平，临床病理特征和预后，但其具有不同的基因变异特征，提示TME分型的背后原因可能是基因变异所致。这些数据为中国肺鳞癌患者的精准免疫治疗之路提供了丰富的证据。
图3. 基于PD-L1和CD8+ TIL表达的四种肿瘤免疫微环境分型结果
摘要：
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
（来源：科学网）
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