INTRODUCTION This study aimed to characterize the tumor-infiltrating immune cells population in Kras/tumor protein 53 (Trp53)-driven lung tumors and to evaluate the combinatorial antitumor effect with MEK inhibitor (MEKi), trametinib, and immunomodulatory monoclonal antibodies (mAbs) targeting either programmed death -1 (PD-1) or programmed cell death ligand 1 (PD-L1) in vivo. METHODS Trp53FloxFlox;KrasG12D/+;Rosa26LSL-Luciferase/LSL-Luciferase (PKL) genetically engineered mice were used to develop autochthonous lung tumors with intratracheal delivery of adenoviral Cre recombinase. Using these tumor-bearing lungs, tumor-infiltrating immune cells were characterized by both mass cytometry and flow cytometry. PKL-mediated immunocompetent syngeneic and transgenic lung cancer mouse models were treated with MEKi alone as well as in combination with either anti-PD-1 or anti-PD-L1 mAbs. Tumor growth and survival outcome were assessed. Finally, immune cell populations within spleens and tumors were evaluated by flow cytometry and immunohistochemistry. RESULTS Myeloid-derived suppressor cells (MDSCs) were significantly augmented in PKL-driven lung tumors compared to normal lungs of tumor-free mice. PD-L1 expression appeared to be highly positive in both lung tumor cells and, particularly MDSCs. The combinatory administration of MEKi with either anti-PD-1 or anti-PD-L1 mAbs synergistically increased antitumor response and survival outcome compared with single-agent therapy in both the PKL-mediated syngeneic and transgenic lung cancer models. Theses combinational treatments resulted in significant increases of tumor-infiltrating CD8+ and CD4+ T cells, whereas attenuation of CD11b+/Gr-1high MDSCs, in particular, Ly6Ghigh polymorphonuclear-MDSCs in the syngeneic model. CONCLUSIONS These findings suggest a potential therapeutic approach for untargetable Kras/p53-driven lung cancers with synergy between targeted therapy using MEKi and immunotherapies.

中文翻译：

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MEK 抑制剂与靶向 PD-1 和 PD-L1 的免疫调节抗体联用可延长 Kras/p53 驱动的肺癌的生存期

引言 本研究旨在表征 Kras/肿瘤蛋白 53 (Trp53) 驱动的肺肿瘤中的肿瘤浸润免疫细胞群，并评估 MEK 抑制剂 (MEKi)、曲美替尼和免疫调节单克隆抗体 (mAb) 靶向的组合抗肿瘤效果体内程序性死亡-1（PD-1）或程序​​性细胞死亡配体1（PD-L1）。方法 Trp53FloxFlox；KrasG12D/+；Rosa26LSL-萤光素酶/LSL-萤光素酶（PKL）基因工程小鼠被用于开发具有腺病毒Cre重组酶气管内递送的本土肺肿瘤。使用这些带有肿瘤的肺，肿瘤浸润免疫细胞的特征在于质谱流式细胞术和流式细胞术。PKL 介导的免疫活性同基因和转基因肺癌小鼠模型单独使用 MEKi 以及与抗 PD-1 或​​抗 PD-L1 单克隆抗体联合治疗。评估肿瘤生长和存活结果。最后，通过流式细胞术和免疫组织化学评估脾脏和肿瘤内的免疫细胞群。结果 与无肿瘤小鼠的正常肺相比，PKL 驱动的肺肿瘤中髓源性抑制细胞 (MDSC) 显着增加。PD-L1 表达似乎在肺肿瘤细胞，尤其是 MDSC 中均呈高度阳性。在 PKL 介导的同基因和转基因肺癌模型中，与单药治疗相比，MEKi 与抗 PD-1 或​​抗 PD-L1 mAb 的联合给药协同增加了抗肿瘤反应和生存结果。这些联合治疗导致肿瘤浸润性 CD8+ 和 CD4+ T 细胞显着增加，而 CD11b+/Gr-1high MDSCs，特别是同基因模型中的 Ly6Ghigh 多形核-MDSCs 减弱。结论这些发现表明了一种潜在的治疗方法，用于不可靶向的 Kras/p53 驱动的肺癌，在使用 MEKi 的靶向治疗和免疫疗法之间具有协同作用。