MEK 抑制剂联合靶向程序性死亡受体 1 和程序性死亡配体 1 的免疫调节抗体可延长 Kras/p53 驱动的肺癌患者的生存时间。
The Combination of MEK Inhibitor With Immunomodulatory Antibodies Targeting Programmed Death 1 and Programmed Death Ligand 1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer.
机构信息
Section of Medical Oncology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut.
Department of Immunobiology, Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, Connecticut.
出版信息
J Thorac Oncol. 2019 Jun;14(6):1046-1060. doi: 10.1016/j.jtho.2019.02.004. Epub 2019 Feb 13.
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
Trp53;Kras;Rosa26 (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-1 MDSCs, in particular, Ly6G 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.
简介
本研究旨在描述 Kras/肿瘤蛋白 53（Trp53）驱动的肺肿瘤中的肿瘤浸润免疫细胞群体，并评估 MEK 抑制剂（MEKi）、曲美替尼与针对程序性死亡受体-1（PD-1）或程序性死亡配体 1（PD-L1）的免疫调节单克隆抗体（mAb）联合应用于体内的抗肿瘤作用。
方法
使用 Trp53;Kras;Rosa26（PKL）基因工程小鼠通过气管内递送腺病毒 Cre 重组酶来发展自发的肺肿瘤。使用这些带瘤肺，通过质谱流式细胞术和流式细胞术来描述肿瘤浸润免疫细胞。在 PKL 介导的免疫活性同基因和转基因肺癌小鼠模型中，单独使用 MEKi 以及联合使用抗 PD-1 或抗 PD-L1 mAb 进行治疗。评估肿瘤生长和生存结果。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体。
结果
髓源性抑制细胞（MDSCs）在 PKL 驱动的肺肿瘤中与无肿瘤小鼠的正常肺相比显著增加。PD-L1 表达似乎在肺肿瘤细胞中高度阳性，尤其是 MDSCs 中。与单一疗法相比，MEKi 联合抗 PD-1 或抗 PD-L1 mAb 的联合治疗在 PKL 介导的同基因和转基因肺癌模型中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 细胞显著增加，而在同基因模型中，CD11b/Gr-1 MDSCs，特别是 Ly6G 多形核 MDSCs 减少。
结论
这些发现表明针对无法靶向治疗的 Kras/p53 驱动的肺癌，靶向治疗使用 MEKi 与免疫疗法联合具有潜在的治疗方法。
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