Cell-of-origin links lung tumor histotype spectrum to immune microenvironment diversity. Mus musculus

Lung cancers exhibit pronounced functional heterogeneity, confounding precision medicine. We studied how the cell-of-origin contributes to phenotypic heterogeneity following conditional expression of KrasG12D and loss of Lkb1 (Kras;Lkb1). Using progenitor cell type-restricted adenoviral-Cre to target cells expressing Surfactant Protein C (SPC) or club cell antigen 10 (CC10), we show that Ad5-CC10-Cre infected mice exhibit a shorter latency compared with Ad5-SPC-Cre cohorts. We further demonstrate that CC10+ cells are the predominant progenitors of adenosquamous carcinoma (ASC) tumors, and give rise to a wider spectrum of histotypes that includes mucinous and acinar adenocarcinomas. Transcriptome analysis shows ASC histotype-specific upregulation of proinflammatory and immunomodulatory genes. This is accompanied with an ASC-specific immunosuppressive environment, consisting of downregulated MHC genes, recruitment of CD11b+ Gr-1+ tumor-associated neutrophils (TANs) and decreased T-cell numbers. We conclude that progenitor cell-specific etiology influences the Kras;Lkb1-driven tumor histopathology spectrum and histotype-specific immune microenvironment. Overall design: Two tumors per mouse from three Kras;Lkb1 mice infected with Ad5-CC10-Cre, two tumors per mouse from three Kras;Lkb1 mice infected with Ad5-SPC-Cre, one tumour per mouse from two Kras;p53 mice infected with Ad5-CC10-Cre, and one tumour per mouse from three Kras;p53 mice infected with Ad5-SPC-Cre were analysed.

肺癌表现出显著的功能异质性，该特性给精准医学的开展带来了阻碍。本研究针对KrasG12D条件性表达且Lkb1缺失（Kras;Lkb1）模型，探究了细胞起源如何影响肿瘤的表型异质性。
本研究利用细胞类型限制性腺病毒-Cre（adenoviral-Cre）靶向表达表面活性蛋白C（Surfactant Protein C, SPC）或克拉拉细胞抗原10（club cell antigen 10, CC10）的细胞，结果显示，感染Ad5-CC10-Cre的小鼠模型的肿瘤潜伏期较Ad5-SPC-Cre组更短。进一步研究发现，CC10阳性细胞是腺鳞癌（adenosquamous carcinoma, ASC）的主要起源细胞，且可分化为包含黏液性腺癌、腺泡性腺癌在内的多种组织学亚型。
转录组分析结果显示，ASC组织学亚型特异性上调促炎基因与免疫调节基因的表达。该特征同时伴随ASC特异性的免疫抑制微环境，具体表现为MHC（主要组织相容性复合体，Major Histocompatibility Complex）基因表达下调、CD11b+Gr-1+肿瘤相关中性粒细胞（tumor-associated neutrophils, TANs）浸润增加以及T细胞数量减少。
综上，本研究表明，细胞起源特异性的病因学特征可影响Kras;Lkb1驱动的肿瘤组织病理学谱及组织学亚型特异性免疫微环境。
实验设计：对以下样本进行分析：3只感染Ad5-CC10-Cre的Kras;Lkb1小鼠，每只小鼠取2个肿瘤样本；3只感染Ad5-SPC-Cre的Kras;Lkb1小鼠，每只小鼠取2个肿瘤样本；2只感染Ad5-CC10-Cre的Kras;p53小鼠，每只小鼠取1个肿瘤样本；3只感染Ad5-SPC-Cre的Kras;p53小鼠，每只小鼠取1个肿瘤样本。