Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma
Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma
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DOI：
10.1158/1078-0432.ccr-16-2554
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发表时间：
2017-06-15
影响因子：
11.5
通讯作者：
Wu, Yi-Long
中科院分区：
文献类型：
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作者：
Dong, Zhong-Yi;Zhong, Wen-Zhao;Wu, Yi-Long
目的：尽管临床研究显示针对非小细胞肺癌（NSCLC）的程序性细胞死亡蛋白-1 （PD-1）和配体（PD-L1）信号传导有希望，但预测哪种亚型患者对检查点阻断有反应的因素尚不完全清楚。实验设计：我们对来自肺腺癌公众（发现组）和内部（验证组）数据库以及免疫治疗患者队列的多维数据类型进行了综合分析，包括基因组、转录组、蛋白质组和临床数据。基因集富集分析（GSEA）用于确定特定亚群之间潜在相关的基因表达特征。结果：我们观察到TP53突变显著增加免疫检查点的表达，激活t效应和干扰素-g信号。更重要的是，TP53/KRAS计算亚组的PD-L1表达增加，PD-L1(+)/CD8A（+）比例最高。与此同时，TP53-或kras突变的肿瘤表现出显著的突变负担增加，并在高平移（TH）队列中特异性富集。对潜在分子机制的进一步分析表明，TP53或KRAS突变改变了一组参与细胞周期调节、DNA复制和损伤修复的基因。最后，通过公开临床试验和本中心前瞻性观察的免疫治疗分析，进一步证实了TP53或KRAS突变患者，特别是同时发生TP53/KRAS突变的患者，PD-1抑制剂的临床获益显著。结论：本工作提示肺腺癌TP53和KRAS突变可能作为指导抗pd -1/PD-L1免疫治疗的一对潜在预测因素。(c) 2016年aacr。
Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-g signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1(+)/CD8A(+). Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. (C) 2016 AACR.