期刊
IMMUNITY
卷 49, 期 4, 页码 764-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2018.09.020
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资金
- National Cancer Institute (NCI) of the National Institutes of Health (NIH) [P30CA042014]
- Biorepository and Molecular Pathology, High Throughput Genomics and Bioinformatics Analysis, and Flow Cytometry Shared Resources
- Immunology, Inflammation, and Infectious Diseases Initiative
- NIH NCI [F99CA223015, R01CA187457]
- Burroughs Wellcome Fund
- NIH [R01CA212415]
- Damon Runyon Cancer Research Foundation [DRR-26-13]
- American Cancer Society [RSG-13-300-01-TBG]
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 Lkb 1 (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.
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