Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression

Chunxiao Xu; Christine M Fillmore; Shohei Koyama; Hongbo Wu; Yanqiu Zhao; Zhao Chen; Grit S Herter-Sprie; Esra A Akbay; Jeremy H Tchaicha; Abigail Altabef; Jacob B Reibel; Zandra Walton; Hongbin Ji; Hideo Watanabe; Pasi A Jänne; Diego H Castrillon; Anil K Rustgi; Adam J Bass; Gordon J Freeman; Robert F Padera; Glenn Dranoff; Peter S Hammerman; Carla F Kim; Kwok-Kin Wong

doi:10.1016/j.ccr.2014.03.033

Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression

Cancer Cell. 2014 May 12;25(5):590-604. doi: 10.1016/j.ccr.2014.03.033. Epub 2014 May 1.

Authors

Chunxiao Xu¹, Christine M Fillmore², Shohei Koyama³, Hongbo Wu⁴, Yanqiu Zhao⁴, Zhao Chen¹, Grit S Herter-Sprie¹, Esra A Akbay¹, Jeremy H Tchaicha¹, Abigail Altabef¹, Jacob B Reibel¹, Zandra Walton⁵, Hongbin Ji⁶, Hideo Watanabe⁷, Pasi A Jänne¹, Diego H Castrillon⁸, Anil K Rustgi⁹, Adam J Bass¹⁰, Gordon J Freeman¹¹, Robert F Padera¹², Glenn Dranoff³, Peter S Hammerman¹³, Carla F Kim¹⁴, Kwok-Kin Wong¹⁵

Affiliations

¹ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Belfer Institute For Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
² Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology and Cancer Vaccine Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁴ Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China.
⁵ Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁸ Department of Pathology and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
⁹ Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
¹⁰ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹² Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: phammerman@partners.org.
¹⁴ Stem Cell Program, Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: carla.kim@childrens.harvard.edu.
¹⁵ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Belfer Institute For Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: kwong1@partners.org.

Abstract

Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1(+)NGFR(+) fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR(+) cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases
Animals
Antigens, Ly / biosynthesis
B-Lymphocytes / immunology
B7-H1 Antigen / biosynthesis*
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / immunology*
Disease Models, Animal
Immune Tolerance / immunology
Keratin-15
Keratin-5 / biosynthesis
Killer Cells, Natural / immunology
Lung / metabolism
Lung Neoplasms / genetics
Lung Neoplasms / immunology*
Lymphocyte Activation / immunology
Macrophages / immunology
Membrane Proteins / biosynthesis
Metabolome
Mice
Neutrophils / immunology
PTEN Phosphohydrolase / genetics*
Phosphoproteins / biosynthesis
Protein Serine-Threonine Kinases / genetics*
Receptor, Nerve Growth Factor / biosynthesis
SOXB1 Transcription Factors / biosynthesis
T-Lymphocytes / immunology
Trans-Activators / biosynthesis
Transcription, Genetic
Tumor Cells, Cultured
Tumor Escape / immunology*

Substances

Antigens, Ly
B7-H1 Antigen
Cd274 protein, mouse
Keratin-15
Keratin-5
Krt15 protein, mouse
Ly6a protein, mouse
Membrane Proteins
Phosphoproteins
Receptor, Nerve Growth Factor
SOXB1 Transcription Factors
Sox2 protein, mouse
Trans-Activators
Trp63 protein, mouse
Protein Serine-Threonine Kinases
Stk11 protein, mouse
AMP-Activated Protein Kinases
PTEN Phosphohydrolase
Pten protein, mouse

Associated data

GEO/GSE54353

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding