Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75235, USA.
Department of Immunology, UT Southwestern Medical Center, Dallas, TX 75235, USA.
Sci Immunol. 2019 Aug 9;4(38). doi: 10.1126/sciimmunol.aav6473.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non-small cell lung cancer by blocking oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand-1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors.
表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂 (TKI) 通过阻断致癌受体信号来快速杀死肿瘤，如非小细胞肺癌相关的肿瘤，是一线治疗方法，但肿瘤常常会复发。在这里，我们观察到，低分割 EGFR TKI 治疗（HypoTKI）比标准的高分割 EGFR TKI 治疗（HyperTKI）更有效，其抗肿瘤作用与预防肿瘤复发有关，依赖于 T 细胞。HypoTKI 通过 Myd88 信号通路触发更强的 I 型干扰素和 CXCL10 的先天感应，从而增强肿瘤特异性 T 细胞浸润和再激活。我们还证明，及时的程序性细胞死亡配体-1（PD-L1）阻断可以与 HypoTKI 协同作用，控制晚期大肿瘤，并有效地限制肿瘤复发，而没有严重的副作用。我们的研究为探索适当的 EGFR TKI 和免疫疗法联合作为治疗 EGFR 驱动肿瘤的一线治疗方法的潜力提供了证据。
