Cell of Origin Links Histotype Spectrum to Immune Microenvironment Diversity in Non-small-Cell Lung Cancer Driven by Mutant Kras and Loss of Lkb1

• Published in: Cell reports (Cambridge) Vol. 18; no. 3; pp. 673 - 684
• Main Authors: Nagaraj, Ashwini S., Lahtela, Jenni, Hemmes, Annabrita, Pellinen, Teijo, Blom, Sami, Devlin, Jennifer R., Salmenkivi, Kaisa, Kallioniemi, Olli, Mäyränpää, Mikko I., Närhi, Katja, Verschuren, Emmy W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17-01-2017; Elsevier
• Subjects: adenosquamous; cell-of-origin; club cell; histopathology; immune microenvironment; Kras; Lkb1; Medicin och hälsovetenskap; non-small-cell lung cancer; tumor-associated neutrophils; immune microenvironment; club cell; tumor-associated neutrophils; histopathology; Kras; Lkb1; adenosquamous; cell-of-origin; non-small-cell lung cancer
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.12.059

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 pro-inflammatory and immunomodulatory genes. This is accompanied by 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.
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•Cell of origin crucially defines tumor proliferation and the histopathology spectrum•CC10+ cells are the predominant progenitors of ASC tumors in Kras;Lkb1 mice•CC10+ cells give rise to pure mucinous and acinar adenocarcinoma histotypes•ASCs exhibit a histotype-specific immunosuppressive microenvironment
Nagaraj et al. demonstrate that the cell of origin defines the NSCLC histopathology spectrum and associated immune microenvironment upon the expression of KrasG12D and loss of the tumor suppressor Lkb1. Significantly, the histopathology rather than the oncogenotype determined immune signatures, suggesting that a deeper understanding of histotype-dependent features is important for clinical decision-making.