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

Gurkan Mollaoglu, Alex Jones, Sarah J. Wait, Anandaroop Mukhopadhyay, Sangmin Jeong, Rahul Arya, Soledad A. Camolotto, Timothy L. Mosbruger, Chris J. Stubben, Christopher J. Conley, Arjun Bhutkar, Jeffery M. Vahrenkamp, Kristofer C. Berrett, Melissa H. Cessna, Thomas E. Lane, Benjamin L. Witt, Mohamed E. Salama, Jason Gertz, Kevin B. Jones, Eric L. SnyderTrudy G. Oliver

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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. Mollaoglu et al. use genetically engineered mouse models of non-small-cell lung cancer (NSCLC) to define the relationship between lineage-defining transcription factors and squamous NSCLC and adenocarcinoma, revealing that this interplay also determines neutrophil recruitment. Depletion of tumor-associated neutrophils (TANs) reduced squamous tumors and promoted adenocarcinoma features, suggesting that the immune microenvironment might contribute to the nature of the tumor.

Original languageEnglish (US)
Pages (from-to)764-779.e9
JournalImmunity
Volume49
Issue number4
DOIs
StatePublished - Oct 16 2018

Keywords

  • CXCL5
  • NKX2-1
  • SOX2
  • adenocarcinoma
  • lung cancer
  • mouse models
  • squamous
  • transdifferentiation
  • tumor immune microenvironment
  • tumor-associated neutrophils

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Mollaoglu, G., Jones, A., Wait, S. J., Mukhopadhyay, A., Jeong, S., Arya, R., Camolotto, S. A., Mosbruger, T. L., Stubben, C. J., Conley, C. J., Bhutkar, A., Vahrenkamp, J. M., Berrett, K. C., Cessna, M. H., Lane, T. E., Witt, B. L., Salama, M. E., Gertz, J., Jones, K. B., ... Oliver, T. G. (2018). The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment. Immunity, 49(4), 764-779.e9. https://doi.org/10.1016/j.immuni.2018.09.020