Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated Pdl1 Expression: Stroma Cells. Mus musculus

Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that bi-allelic inactivation of Lkb1 and Pten in the mouse lung led to SCC that recapitulated the histology, gene expression and microenvironment found in human disease. Lkb1/Pten-null (LP) tumors expressed the squamous markers Krt5, p63 and Sox2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. Sca1+/Ngfr+ fractions were enriched for tumor propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and Ngfr+ cells in human SCCs highly expressed Pdl1, suggesting a novel mechanism of immune escape for TPCs. We used microarrays to detail the gene expression profles among lung SCC tumor epitheial cell, lung ADC tumor epithelia cell and normal epithelial cells. Overall design: Kras tumor stroma cells and LP tumor stroma cells were sorted by FACS, the cells were gated as EpCAM-/CD45+/CD31+

肺鳞状细胞癌（SCC）是一类致死性疾病，当前治疗手段仍存在显著不足。本研究证实，在小鼠肺部双等位基因失活Lkb1与Pten，可构建出能够重现人类该病组织学特征、基因表达谱与肿瘤微环境的肺鳞状细胞癌模型。Lkb1/Pten双缺失（LP）肿瘤表达鳞状细胞标志物Krt5、p63及Sox2，其转录组特征与人肺鳞状细胞癌的基底亚型高度相似。与小鼠肺腺癌（ADC）不同，LP肿瘤的免疫细胞群中肿瘤相关中性粒细胞呈现显著富集。Sca1+/Ngfr+细胞组分中富集有肿瘤增殖细胞（TPCs），该类细胞可在原位移植实验中实现肿瘤的连续传代移植。LP模型中的肿瘤增殖细胞与人类肺鳞状细胞癌中的Ngfr+细胞均高表达Pdl1，这提示了肿瘤增殖细胞的一种新型免疫逃逸机制。本研究通过微阵列技术详细解析了肺鳞状细胞癌肿瘤上皮细胞、肺腺癌肿瘤上皮细胞与正常上皮细胞的基因表达谱。实验设计：通过荧光激活细胞分选（FACS）分离获取Kras肿瘤间质细胞与LP肿瘤间质细胞，分选门控策略为EpCAM-/CD45+/CD31+