title: Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells.
abstract: BACKGROUND
  The T-cell inhibitory molecule PD-L1 (B7-H1, CD274) is expressed on tumor cells of a subset of breast cancer patients. However, the mechanism that regulates PD-L1 expression in this group of patients is still not well-identified.
  
  
  METHODS
  We have used loss and gain of function gene manipulation approach, multi-parametric flow cytometry, large scale gene expression dataset analysis and immunohistochemistry of breast cancer tissue sections.
  
  
  RESULTS
  Induction of epithelial to mesenchymal transition (EMT) in human mammary epithelial cells upregulated PD-L1 expression, which was dependent mainly on the activation of the PI3K/AKT pathway. Interestingly, gene expression signatures available from large cohort of breast tumors showed a significant correlation between EMT score and the PD-L1 mRNA level (p < 0.001). Strikingly, very strong association (p < 0.0001) was found between PD-L1 expression and claudin-low subset of breast cancer, which is known to have high EMT score. On the protein level, significant correlation was found between PD-L1 expression and standard markers of EMT (p = 0.005) in 67 breast cancer patients. Importantly, specific downregulation of PD-L1 in claudin-low breast cancer cells showed signs of EMT reversal as manifested by CD44 and Vimentin downregulation and CD24 upregulation.
  
  
  CONCLUSIONS
  We have demonstrated a bidirectional effect between EMT status and PD-L1 expression especially in claudin-low subtype of breast cancer cells. Our findings highlights the potential dual benefit of anti-PD-L1 particularly in this subset of breast cancer patients that will likely benefit more from anti-PD-L1 targeted therapy as well as in monitoring biological changes upon treatment.
authors.affiliation: Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. absuliman@kfshrc.edu.sa.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alsuliman
authors.affiliation: Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. dcolakkaya@kfshrc.edu.sa.
authors.forename: Dilek
authors.initials: D
authors.lastname: Colak
authors.affiliation: Department of Biostatistics, Epidemiology and Scientific Computing, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. n3509885@kfshrc.edu.sa.
authors.forename: Olfat
authors.initials: O
authors.lastname: Al-Harazi
authors.affiliation: Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. n3508575@kfshrc.edu.sa.
authors.forename: Hanaa
authors.initials: H
authors.lastname: Fitwi
authors.affiliation: Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. tulbah@kfshrc.edu.sa.
authors.forename: Asma
authors.initials: A
authors.lastname: Tulbah
authors.affiliation: Oncology Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. ttwegieri@kfshrc.edu.sa.
authors.forename: Taher
authors.initials: T
authors.lastname: Al-Tweigeri
authors.affiliation: Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. malwan@kfshrc.edu.sa.|College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia. malwan@kfshrc.edu.sa.
authors.forename: Monther
authors.initials: M
authors.lastname: Al-Alwan
authors.affiliation: Stem Cell & Tissue Re-engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. hghebeh@kfshrc.edu.sa.|College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia. hghebeh@kfshrc.edu.sa.
authors.forename: Hazem
authors.initials: H
authors.lastname: Ghebeh
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D060890:B7-H1 Antigen; D057167:Claudins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases