Selenz Carolin, Compes Anik, Nill Marieke, Borchmann Sven, Odenthal Margarete, Florin Alexandra, Brägelmann Johannes, Büttner Reinhard, Meder Lydia, Ullrich Roland T
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
Cancers (Basel). 2022 Aug 16;14(16):3943. doi: 10.3390/cancers14163943.
EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC.
表皮生长因子受体（EGFR）驱动的非小细胞肺癌（NSCLC）患者目前接受靶向EGFR的酪氨酸激酶抑制剂（TKI）治疗，如厄洛替尼或奥希替尼。尽管TKI治疗初期反应良好，但大多数患者会对致癌基因靶向治疗产生耐药性，肿瘤仍会进展。随着针对介导免疫抑制微环境的免疫检查点抑制剂（如PD-1）的开发，免疫治疗方法试图恢复肿瘤中的促炎免疫反应。然而，该策略在EGFR驱动的NSCLC中仅显示出有限的益处。由于对EGFR靶向治疗对肿瘤微环境（TME）中免疫细胞的影响了解不足，将EGFR抑制与免疫治疗相结合以刺激免疫反应并克服治疗耐药性的方法一直有限。在此，我们研究了厄洛替尼抑制EGFR对TME的影响及其对免疫细胞浸润抗肿瘤反应的作用。为此，我们使用转基因条件小鼠模型来研究EGFR驱动的NSCLC肿瘤中的免疫特征。我们发现，EGFR抑制介导了免疫细胞的更高浸润，并增加了肿瘤中T细胞的局部增殖。此外，抑制EGFR信号传导导致TME中免疫细胞的激活增加。最引人注目的是，在EGFR驱动的NSCLC转基因小鼠模型中，同时联合阻断EGFR和抗PD-1（aPD-1）可增强肿瘤治疗反应。因此，我们的研究结果表明，EGFR抑制可促进TME中活跃的促炎免疫细胞浸润，同时改善EGFR驱动的NSCLC对免疫检查点抑制剂的反应。
