Impact of EGFR-TKIs combined with PD-L1 antibody on the lung tissue of EGFR-driven tumor-bearing mice
Impact of EGFR-TKIs combined with PD-L1 antibody on the lung tissue of EGFR-driven tumor-bearing mice
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EGFR-TKIs联合PD-L1抗体对EGFR荷瘤小鼠肺组织的影响
DOI：
10.1016/j.lungcan.2019.09.016
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发表时间：
2019-11-01
期刊：
影响因子：
5.3
通讯作者：
Zhou, Caicun
中科院分区：
文献类型：
--
作者：
Jia, Yijun;Zhao, Sha;Zhou, Caicun
目的：EGFR靶向酪氨酸激酶抑制剂（TKI）已成为EGFR突变非小细胞肺癌患者的标准治疗。然而，大多数患者最终会产生耐药性。随着靶向程序性细胞死亡受体/配体1（PD-1/PD-L1）的免疫检查点抑制剂的开发，人们对开发联合策略的兴趣越来越大。然而，人们担心PD-（L）1抑制剂和EGFR-TKI的组合可能与肺炎风险增加相关。因此，我们利用一个建立的EGFR驱动的荷瘤小鼠模型，以调查是否联合会诱导小鼠肺组织中的肺炎。材料和方法：小鼠用PD-L1抗体和EGFR-TKI，包括第一代吉非替尼和第三代奥希替尼的单药治疗或联合治疗。结果与结论：奥希替尼联合抗PD-L1治疗组肺组织H & E染色病理分级炎症评分最高，髓过氧化物酶阳性细胞百分比最高。然而，吉非替尼和抗PD-L1联合治疗似乎不会增加小鼠肺炎的水平。在奥希替尼和抗PD-L1联合治疗组中，BALF中的总细胞计数、中性粒细胞计数和总蛋白浓度也显著增加。我们接下来评估了BALF中的促炎因子。奥希替尼和抗PD-L1联合治疗组的IFN-γ、IL-2、IL-5、TNF-α和IL-12 p70水平升高。不同给药顺序的比较表明，接受奥希替尼治疗后再接受PD-L1抗体治疗的小鼠未显示出明显的肺部炎症。我们的研究结果表明，奥希替尼而不是吉非替尼联合抗PD-L1治疗可能导致EGFR突变荷瘤小鼠模型的肺损伤。EGFR-TKI和PD-L1抗体联合给药的顺序和时间可能会影响肺炎的严重程度。
Objectives: EGFR-targeted tyrosine kinase inhibitors (TKIs) have been the standard treatment for non-small cell lung cancer patients with EGFR mutations. However, most patients eventually develop resistance. With the development of immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1), there is a growing interest in developing combination strategies. However, there are concerns that the combination of a PD-(L)1 inhibitor and EGFR-TKI may be associated with an increased risk of pneumonitis. Therefore, we utilized an established EGFR-driven tumor-bearing mouse model to investigate whether the combination would induce pneumonitis in mouse lung tissue.Materials and Methods: Mice were treated with monotherapy or combined therapy of PD-L1 antibody and EGFR-TKIs including first-generation gefitinib and third-generation osimertinib. Bronchoalveolar lavage fluids (BALFs) and lung tissues were collected for analysis at the end of treatment.Results and Conclusion: The osimertinib and anti-PD-L1 combined treatment group had the highest inflammation scores in pathologic grades of H&E staining of lung tissue and had the highest percentages of myeloperoxidase positive cells. However, combining gefitinib and anti-PD-L1 treatment appeared to not increase the level of pneumonitis in mice. Total cell counts, neutrophil counts and total protein concentration in BALFs were also significantly increased in the osimertinib and anti-PD-L1 combined treatment group. We next evaluated proinflammatory factors in BALFs. The levels of IFN-gamma, IL-2, IL-5, TNF-alpha and IL-12p70 were increased in osimertinib and anti-PD-L1 combined treatment group. Comparison of different sequences of drug administration demonstrated that mice treated with osimertinib followed by PD-L1 antibody did not show evident lung inflammation. Our findings indicate that osimertinib, rather than gefitinib combined with anti-PD-L1 treatment could lead to lung injury in an EGFR mutated tumor-bearing mouse model. The sequence and timing of combining EGFR-TKI and PD-L1 antibody may influence the severity of pneumonitis.