Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors
Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors
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DOI：
10.1186/s40425-019-0643-8
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发表时间：
2019-07-10
影响因子：
10.9
通讯作者：
Politi, Katerina
中科院分区：
文献类型：
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作者：
Ayeni, Deborah;Miller, Braden;Politi, Katerina
背景：表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）如厄洛替尼可有效治疗 EGFR 突变肺癌患者；然而，耐药性不可避免地出现。由于对厄洛替尼对肿瘤浸润免疫细胞的影响了解有限，结合免疫疗法和靶向治疗来克服或延缓耐药性的方法受到阻碍。方法：使用小鼠模型，我们研究了厄洛替尼治疗前后突变型 EGFR 驱动的肺肿瘤的免疫学特征。结果：我们发现厄洛替尼触发了炎症 T 细胞向肺部的募集并加速了肺泡巨噬细胞的成熟。有趣的是，这种表型可以通过剥夺 EGFR 癌基因介导的肿瘤消退来重现，表明仅肿瘤消退就足以产生这些免疫刺激作用。我们还发现，通过将厄洛替尼治疗与抗 PD-1 和/或 CD40 激动剂相结合来进一步增强炎症细胞的功能和丰度，并没有改善 EGFR 驱动的小鼠模型的生存率。 结论：我们的研究结果为理解 TKI 对肿瘤微环境的影响奠定了基础，并强调了研究靶向和免疫治疗组合策略治疗 EGFR 突变肺癌的重要性。
Background: Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells.Methods: Using mouse models, we studied the immunological profile of mutant EGFR-driven lung tumors before and after erlotinib treatment.Results: We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs and increased maturation of alveolar macrophages. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. We also found that further efforts to boost the function and abundance of inflammatory cells, by combining erlotinib treatment with anti-PD-1 and/or a CD40 agonist, did not improve survival in an EGFR-driven mouse model.Conclusions: Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlight the importance of investigating targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.