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.

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

  • 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
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • Pten protein, mouse

Associated data

  • GEO/GSE54353