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Immunity. 2018 Oct 16;49(4):764-779.e9. doi: 10.1016/j.immuni.2018.09.020.

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

Author information

1
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
2
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
3
Huntsman Cancer Institute, Bioinformatics Shared Resource, Salt Lake City, UT 84112, USA.
4
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5
Intermountain Biorepository, Intermountain Healthcare, Salt Lake City, UT 84111, USA.
6
Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA; ARUP Laboratories at University of Utah, Salt Lake City, UT 84108, USA.
7
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA.
8
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA; Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.
9
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. Electronic address: trudy.oliver@hci.utah.edu.

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.

KEYWORDS:

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

PMID:
30332632
PMCID:
PMC6197489
DOI:
10.1016/j.immuni.2018.09.020
[Indexed for MEDLINE]
Free PMC Article

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