TY - JOUR
T1 - The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment
AU - Mollaoglu, Gurkan
AU - Jones, Alex
AU - Wait, Sarah J.
AU - Mukhopadhyay, Anandaroop
AU - Jeong, Sangmin
AU - Arya, Rahul
AU - Camolotto, Soledad A.
AU - Mosbruger, Timothy L.
AU - Stubben, Chris J.
AU - Conley, Christopher J.
AU - Bhutkar, Arjun
AU - Vahrenkamp, Jeffery M.
AU - Berrett, Kristofer C.
AU - Cessna, Melissa H.
AU - Lane, Thomas E.
AU - Witt, Benjamin L.
AU - Salama, Mohamed E.
AU - Gertz, Jason
AU - Jones, Kevin B.
AU - Snyder, Eric L.
AU - Oliver, Trudy G.
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/10/16
Y1 - 2018/10/16
N2 - 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.
AB - 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.
KW - CXCL5
KW - NKX2-1
KW - SOX2
KW - adenocarcinoma
KW - lung cancer
KW - mouse models
KW - squamous
KW - transdifferentiation
KW - tumor immune microenvironment
KW - tumor-associated neutrophils
UR - http://www.scopus.com/inward/record.url?scp=85054462342&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054462342&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2018.09.020
DO - 10.1016/j.immuni.2018.09.020
M3 - Article
C2 - 30332632
AN - SCOPUS:85054462342
SN - 1074-7613
VL - 49
SP - 764-779.e9
JO - Immunity
JF - Immunity
IS - 4
ER -