title: Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression.
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.
authors.affiliation: 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.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Fillmore
authors.affiliation: 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.
authors.forename: Shohei
authors.initials: S
authors.lastname: Koyama
authors.affiliation: Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, China.
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Grit S
authors.initials: GS
authors.lastname: Herter-Sprie
authors.affiliation: 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.
authors.forename: Esra A
authors.initials: EA
authors.lastname: Akbay
authors.affiliation: 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.
authors.forename: Jeremy H
authors.initials: JH
authors.lastname: Tchaicha
authors.affiliation: 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.
authors.forename: Abigail
authors.initials: A
authors.lastname: Altabef
authors.affiliation: 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.
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Reibel
authors.affiliation: Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zandra
authors.initials: Z
authors.lastname: Walton
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Cancer Program, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Hideo
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: 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.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Department of Pathology and Simmons Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
authors.affiliation: Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: 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.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.affiliation: 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.
authors.forename: Glenn
authors.initials: G
authors.lastname: Dranoff
authors.affiliation: 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.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: 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.
authors.forename: Carla F
authors.initials: CF
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology; D060890:B7-H1 Antigen / Q000096:biosynthesis*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D007108:Immune Tolerance / Q000276:immunology; D053569:Keratin-15; D053555:Keratin-5 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis; D055442:Metabolome; D051379:Mice; D009504:Neutrophils / Q000276:immunology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010750:Phosphoproteins / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020800:Receptor, Nerve Growth Factor / Q000096:biosynthesis; D055748:SOXB1 Transcription Factors / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000096:biosynthesis; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000950:Antigens, Ly; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D053569:Keratin-15; D053555:Keratin-5; C492053:Krt15 protein, mouse; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D020800:Receptor, Nerve Growth Factor; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse