Epithelial-Mesenchymal Transition Is Associated with a Distinct Tumor Microenvironment Including Elevation of Inflammatory Signals and Multiple Immune Checkpoints in Lung Adenocarcinoma.
Epithelial-Mesenchymal Transition Is Associated with a Distinct Tumor Microenvironment Including Elevation of Inflammatory Signals and Multiple Immune Checkpoints in Lung Adenocarcinoma.
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DOI：
10.1158/1078-0432.ccr-15-1434
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发表时间：
2016-07-15
期刊：
影响因子：
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通讯作者：
Gibbons DL
中科院分区：
文献类型：
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作者：
Lou Y;Diao L;Cuentas ER;Denning WL;Chen L;Fan YH;Byers LA;Wang J;Papadimitrakopoulou VA;Behrens C;Rodriguez JC;Hwu P;Wistuba II;Heymach JV;Gibbons DL
靶向免疫检查点（如PD-1或PD-L1）的药物在NSCLC治疗中取得了令人鼓舞的结果。然而，只有一组选定的患者对这些干预措施作出反应。鉴定预测免疫检查点阻断的临床益处的生物标志物对于这些药物的成功临床转化至关重要。我们对三个独立的大型数据集进行了综合分析，包括肺腺癌的癌症基因组图谱（TCGA）和MD安德森癌症中心的两个数据集，耐药模式和致癌信号通路的评估胸部癌症（称为前景）和生物标志物整合的肺癌靶向治疗方法（称为BATTLE-1）。综合分析mRNA基因表达、反相蛋白阵列（RPPA）、免疫组化及与临床资料的相关性。上皮-间质转化（EMT）与肺腺癌的炎性肿瘤微环境高度相关，与肿瘤突变负荷无关。我们发现免疫激活与多种靶向免疫检查点分子的升高共存，包括PD-L1、PD-L2、PD-1、TIM-3、B7-H3、BTLA和CTLA-4，沿着显示EMT表型的肺腺癌中CD 4 + Foxp 3+调节性T细胞的肿瘤浸润增加。此外，我们确定B7-H3作为NSCLC的预后标志物。EMT状态与炎性肿瘤微环境之间的强相关性以及多个可靶向免疫检查点分子的升高，保证了进一步研究使用EMT作为NSCLC和可能广泛的其他癌症中免疫检查点阻断剂和其他免疫疗法的预测生物标志物。
Promising results in the treatment of NSCLC have been seen with agents targeting immune checkpoints, such as PD-1 or PD-L1. However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune checkpoint blockade is critical to successful clinical translation of these agents. We conducted an integrated analysis of three independent large datasets, including The Cancer Genome Atlas (TCGA) of lung adenocarcinoma and two datasets from MD Anderson Cancer Center, Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (named PROSPECT) and Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (named BATTLE-1). Comprehensive analysis of mRNA gene expression, reverse phase protein array (RPPA), immunohistochemistry and correlation with clinical data were performed. Epithelial-mesenchymal transition (EMT) is highly associated with an inflammatory tumor microenvironment in lung adenocarcinoma, independent of tumor mutational burden. We found immune activation co-existent with elevation of multiple targetable immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, B7-H3, BTLA and CTLA-4, along with increases in tumor infiltration by CD4+Foxp3+ regulatory T cells in lung adenocarcinomas that displayed an EMT phenotype. Furthermore, we identify B7-H3 as a prognostic marker for NSCLC. The strong association between EMT status and an inflammatory tumor microenvironment with elevation of multiple targetable immune checkpoint molecules warrants further investigation of using EMT as a predictive biomarker for immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly a broad range of other cancers.