Continuous targeted kinase inhibitors treatment induces upregulation of PD-L1 in resistant NSCLC
Continuous targeted kinase inhibitors treatment induces upregulation of PD-L1 in resistant NSCLC
复制标题
连续靶向激酶抑制剂治疗可诱导耐药 NSCLC 中 PD-L1 上调
DOI：
10.1038/s41598-018-38068-3
复制
发表时间：
2019-03-06
影响因子：
4.6
通讯作者：
Wang, Yongsheng
中科院分区：
文献类型：
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作者：
Jiang, Li;Guo, Fuchun;Wang, Yongsheng
尽管存在耐药性，但第一代表皮生长因子受体（EGFR）靶向激酶抑制剂（TKI）仍用于选定的非小细胞肺癌（NSCLC）患者。基于程序性细胞死亡受体配体1（PD-L1）与EGFR信号通路的相关性，持续TKI治疗是否会影响疾病进展后的PD-L1表达尚不清楚。为了研究持续TKI治疗后TKI耐药NSCLC中PD-L1表达的潜在变化，我们治疗H1975和HCC 827超过一个月，并探讨对免疫细胞的可能影响以及潜在的生物学机制。我们发现持续暴露于TKI诱导H1975和HCC 827中PD-L1的上调。此外，PD-L1上调显著抑制T细胞增殖并轻微促进T细胞凋亡。我们观察到STAT 3和ERK 1/2的激活与PD-L1的上调一起沿着。通过通路抑制剂，我们发现ERK 1/2通路参与诱导耐药肺癌中PD-L1的产生。本研究提供了临床前证据，表明持续TKI治疗可能诱导耐药NSCLC中的PD-L1表达，导致T细胞功能抑制和免疫逃逸。应考虑使用ERK 1/2通路抑制剂、PD-L1/PD-1抑制剂或联合策略逆转NSCLC患者对TKI的耐药性。
First-generation epidermal growth factor receptor (EGFR) targeted kinase inhibitors (TKIs) are still used in selected non-small cell lung cancer (NSCLC) patients despite the resistance. Based on the correlation of programmed cell death receptor ligand 1 (PD-L1) and EGFR signaling pathway, whether continuous TKIs treatment will affect PD-L1 expression after disease progression remains unclear. To investigate the potential change of PD-L1 expression in TKI-resistant NSCLC after continuous TKIs treatment, we treated H1975 and HCC827 for more than one month and explored the possible effect on immune cells as well as underlying biological mechanisms. We found that continuous exposure to TKIs induced upregulation of PD-L1 in H1975 and HCC827. Moreover, PD-L1 upregulation significantly inhibited proliferation and slightly promoted apoptosis of T cells. We observed the activation of STAT3 and ERK1/2 along with the PD-L1 upregulation. With the pathway inhibitors, we found ERK1/2 pathway involved in inducing PD-L1 in resistant lung cancer. This study provides preclinical evidence that continuous TKIs treatment may induce PD-L1 expression in resistant NSCLC, resulting in the suppression of T cell function and immune escape. ERK1/2 pathway inhibitors, PD-L1/PD-1 inhibitors or combination strategies should be considered to reverse the resistance to TKIs in NSCLC patients.