Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
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DOI：
10.1158/2159-8290.cd-13-0310
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发表时间：
2013-12
期刊：
影响因子：
28.2
通讯作者：
Wong KK
中科院分区：
文献类型：
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作者：
Akbay EA;Koyama S;Carretero J;Altabef A;Tchaicha JH;Christensen CL;Mikse OR;Cherniack AD;Beauchamp EM;Pugh TJ;Wilkerson MD;Fecci PE;Butaney M;Reibel JB;Soucheray M;Cohoon TJ;Janne PA;Meyerson M;Hayes DN;Shapiro GI;Shimamura T;Sholl LM;Rodig SJ;Freeman GJ;Hammerman PS;Dranoff G;Wong KK
程序性死亡（PD）-1阻断剂在肺癌治疗中的成功表明，免疫逃逸机制有助于肺肿瘤的发病机制。我们确定了表皮生长因子受体（EGFR）通路激活与免疫抑制特征之间的相关性，免疫抑制特征表现为PD-1、PD-L1、细胞毒性T淋巴细胞抗原-4（CTLA-4）和多种促肿瘤炎性细胞因子的上调。我们在EGFR驱动的肺癌小鼠模型中观察到细胞毒性T细胞减少和T细胞耗竭标志物增加。PD-1抗体阻断通过增强效应T细胞功能和降低促肿瘤细胞因子水平，改善了EGFR驱动的腺癌小鼠的存活率。支气管上皮细胞中突变型EGFR的表达可诱导PD-L1，EGFR抑制剂可降低EGFR活化的非小细胞肺癌细胞系中PD-L1的表达。这些数据表明，致癌EGFR信号转导重塑肿瘤微环境以触发免疫逃逸，并在机制上将治疗应答与PD-1抑制联系起来。
The success in lung cancer therapy with Programmed Death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between Epidermal Growth Factor Receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, cytotoxic T lymphocyte antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased cytotoxic T cells and increased markers of T cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape, and mechanistically link treatment response to PD-1 inhibition.