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

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2018 Oct 18

PMID 30332632

Citations 107

Authors

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 Snyder

Trudy G Oliver

Affiliations

Soon will be listed here.

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.

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References

Steele C, Karim S, Leach J, Bailey P, Upstill-Goddard R, Rishi L . CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2016; 29(6):832-845. PMC: 4912354. DOI: 10.1016/j.ccell.2016.04.014. View

Van de Laar E, Clifford M, Hasenoeder S, Kim B, Wang D, Lee S . Cell surface marker profiling of human tracheal basal cells reveals distinct subpopulations, identifies MST1/MSP as a mitogenic signal, and identifies new biomarkers for lung squamous cell carcinomas. Respir Res. 2015; 15:160. PMC: 4343068. DOI: 10.1186/s12931-014-0160-8. View

Koyama S, Akbay E, Li Y, Aref A, Skoulidis F, Herter-Sprie G . STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment. Cancer Res. 2016; 76(5):999-1008. PMC: 4775354. DOI: 10.1158/0008-5472.CAN-15-1439. View

Tanaka H, Yanagisawa K, Shinjo K, Taguchi A, Maeno K, Tomida S . Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer Res. 2007; 67(13):6007-11. DOI: 10.1158/0008-5472.CAN-06-4774. View

Busch S, Hanke M, Kargl J, Metz H, MacPherson D, Houghton A . Lung Cancer Subtypes Generate Unique Immune Responses. J Immunol. 2016; 197(11):4493-4503. PMC: 5116260. DOI: 10.4049/jimmunol.1600576. View

Bezzi M, Seitzer N, Ishikawa T, Reschke M, Chen M, Wang G . Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms. Nat Med. 2018; 24(2):165-175. DOI: 10.1038/nm.4463. View

Young N, Crowley D, Jacks T . Uncoupling cancer mutations reveals critical timing of p53 loss in sarcomagenesis. Cancer Res. 2011; 71(11):4040-7. PMC: 3160277. DOI: 10.1158/0008-5472.CAN-10-4563. View

Tata P, Chow R, Saladi S, Tata A, Konkimalla A, Bara A . Developmental History Provides a Roadmap for the Emergence of Tumor Plasticity. Dev Cell. 2018; 44(6):679-693.e5. PMC: 5875457. DOI: 10.1016/j.devcel.2018.02.024. View

Fridlender Z, Sun J, Mishalian I, Singhal S, Cheng G, Kapoor V . Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One. 2012; 7(2):e31524. PMC: 3279406. DOI: 10.1371/journal.pone.0031524. View

10.

Jackson E, Willis N, Mercer K, Bronson R, Crowley D, Montoya R . Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 2001; 15(24):3243-8. PMC: 312845. DOI: 10.1101/gad.943001. View

11.

Schonhuber N, Seidler B, Schuck K, Veltkamp C, Schachtler C, Zukowska M . A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat Med. 2014; 20(11):1340-1347. PMC: 4270133. DOI: 10.1038/nm.3646. View

12.

Mukhopadhyay A, Berrett K, Kc U, Clair P, Pop S, Carr S . Sox2 cooperates with Lkb1 loss in a mouse model of squamous cell lung cancer. Cell Rep. 2014; 8(1):40-9. PMC: 4410849. DOI: 10.1016/j.celrep.2014.05.036. View

13.

Templeton A, McNamara M, Seruga B, Vera-Badillo F, Aneja P, Ocana A . Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst. 2014; 106(6):dju124. DOI: 10.1093/jnci/dju124. View

14.

Kargl J, Busch S, Yang G, Kim K, Hanke M, Metz H . Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat Commun. 2017; 8:14381. PMC: 5296654. DOI: 10.1038/ncomms14381. View

15.

Eruslanov E, Bhojnagarwala P, Quatromoni J, Stephen T, Ranganathan A, Deshpande C . Tumor-associated neutrophils stimulate T cell responses in early-stage human lung cancer. J Clin Invest. 2014; 124(12):5466-80. PMC: 4348966. DOI: 10.1172/JCI77053. View

16.

Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A . Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet. 2001; 29(4):418-25. DOI: 10.1038/ng747. View

17.

Campbell E, Bruyninckx W, Kelly C, Glover L, McNamee E, Bowers B . Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation. Immunity. 2014; 40(1):66-77. PMC: 3951457. DOI: 10.1016/j.immuni.2013.11.020. View

18.

Bender Kim C, Jackson E, Woolfenden A, Lawrence S, Babar I, Vogel S . Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell. 2005; 121(6):823-35. DOI: 10.1016/j.cell.2005.03.032. View

19.

Hou S, Han X, Ji H . Squamous Transition of Lung Adenocarcinoma and Drug Resistance. Trends Cancer. 2017; 2(9):463-466. DOI: 10.1016/j.trecan.2016.08.002. View

20.

Zheng H, Ying H, Yan H, Kimmelman A, Hiller D, Chen A . p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature. 2008; 455(7216):1129-33. PMC: 4051433. DOI: 10.1038/nature07443. View