Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer.
Immune-Modulation by Epidermal Growth Factor Receptor Inhibitors: Implication on Anti-Tumor Immunity in Lung Cancer.
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DOI：
10.1371/journal.pone.0160004
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Perez-Soler R
中科院分区：
文献类型：
--
作者：
Im JS;Herrmann AC;Bernatchez C;Haymaker C;Molldrem JJ;Hong WK;Perez-Soler R
皮肤毒性是表皮生长因子受体（EGFR）抑制剂引起的最常见的毒性，并且与临床疗效相关。由于 EGFR 抑制剂增强受影响皮肤角质形成细胞中抗原呈递分子的表达，因此它们可能同时促进肺癌肿瘤细胞中的新抗原呈递，从而有助于抗肿瘤免疫。在这里，我们研究了 EGFR 抑制剂厄洛替尼对皮肤角质形成细胞和肺癌细胞系的抗原呈递分子和 PD-L1（重要的免疫检查点蛋白）的调节作用，以描绘 EGFR 信号通路抑制和潜在抗肿瘤免疫之间的联系。厄洛替尼上调 IFNγ 处理的角质形成细胞上的 MHC-I 和 MHC-II 蛋白，但消除了 IFNγ 诱导的 PD-L1 表达，表明浸润性自身反应性 T 细胞在受影响皮肤角质形成细胞损伤中的潜在作用。有趣的是，在对厄洛替尼敏感的肺癌细胞系中，MHC-I、MHC-II 和 PD-L1 的表面表达更常见地响应 IFNγ 上调，但厄洛替尼仅抑制 PD-L1 的表达。此外，厄洛替尼显着增加 T 细胞介导的对肺癌细胞的细胞毒性。最后，对《癌细胞系百科全书》中186个肺癌细胞系基因表达数据集的分析表明，PD-L1的过度表达与对厄洛替尼的敏感性以及抗原呈递途径和IFNγ信号通路相关基因的较高表达有关。我们的研究结果表明，EGFR 抑制剂可以通过打破耐受性来促进抗肿瘤适应性免疫反应，特别是在 EGFR 驱动的肺癌中，这种耐受性与 PD-L1 以及与抗原呈递和炎症相关的基因的过度表达有关。
Skin toxicity is the most common toxicity caused by Epidermal Growth Factor Receptor (EGFR) inhibitors, and has been associated with clinical efficacy. As EGFR inhibitors enhance the expression of antigen presenting molecules in affected skin keratinocytes, they may concurrently facilitate neo-antigen presentation in lung cancer tumor cells contributing to anti-tumor immunity. Here, we investigated the modulatory effect of the EGFR inhibitor, erlotinib on antigen presenting molecules and PD-L1, prominent immune checkpoint protein, of skin keratinocytes and lung cancer cell lines to delineate the link between EGFR signaling pathway inhibition and potential anti-tumor immunity. Erlotinib up-regulated MHC-I and MHC-II proteins on IFNγ treated keratinocytes but abrogated IFNγ-induced expression of PD-L1, suggesting the potential role of infiltrating autoreactive T cells in the damage of keratinocytes in affected skin. Interestingly, the surface expression of MHC-I, MHC-II, and PD-L1 was up-regulated in response to IFNγ more often in lung cancer cell lines sensitive to erlotinib, but only expression of PD-L1 was inhibited by erlotinib. Further, erlotinib significantly increased T cell mediated cytotoxicity on lung cancer cells. Lastly, the analysis of gene expression dataset of 186 lung cancer cell lines from Cancer Cell Line Encyclopedia demonstrated that overexpression of PD-L1 was associated with sensitivity to erlotinib and higher expression of genes related to antigen presenting pathways and IFNγ signaling pathway. Our findings suggest that the EGFR inhibitors can facilitate anti-tumor adaptive immune responses by breaking tolerance especially in EGFR driven lung cancer that are associated with overexpression of PD-L1 and genes related to antigen presentation and inflammation.