The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment.

Journal Article (Journal Article)

The major types of non-small-cell lung cancer (NSCLC)-squamous cell carcinoma and adenocarcinoma-have distinct immune microenvironments. We developed a genetic model of squamous NSCLC on the basis of overexpression of the transcription factor Sox2, which specifies lung basal cell fate, and loss of the tumor suppressor Lkb1 (SL mice). SL tumors recapitulated gene-expression and immune-infiltrate features of human squamous NSCLC; such features included enrichment of tumor-associated neutrophils (TANs) and decreased expression of NKX2-1, a transcriptional regulator that specifies alveolar cell fate. In Kras-driven adenocarcinomas, mis-expression of Sox2 or loss of Nkx2-1 led to TAN recruitment. TAN recruitment involved SOX2-mediated production of the chemokine CXCL5. Deletion of Nkx2-1 in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. Depletion of TANs in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Thus, lineage-defining transcription factors determine the tumor immune microenvironment, which in turn might impact the nature of the tumor.

Full Text

Duke Authors

Cited Authors

  • Mollaoglu, G; Jones, A; Wait, SJ; Mukhopadhyay, A; Jeong, S; Arya, R; Camolotto, SA; Mosbruger, TL; Stubben, CJ; Conley, CJ; Bhutkar, A; Vahrenkamp, JM; Berrett, KC; Cessna, MH; Lane, TE; Witt, BL; Salama, ME; Gertz, J; Jones, KB; Snyder, EL; Oliver, TG

Published Date

  • October 16, 2018

Published In

Volume / Issue

  • 49 / 4

Start / End Page

  • 764 - 779.e9

PubMed ID

  • 30332632

Pubmed Central ID

  • PMC6197489

Electronic International Standard Serial Number (EISSN)

  • 1097-4180

Digital Object Identifier (DOI)

  • 10.1016/j.immuni.2018.09.020

Language

  • eng

Conference Location

  • United States