Chemotherapy-Induced PDL-1 Expression in Cancer-Associated Fibroblasts Promotes Chemoresistance in NSCLC

Details

• Personal Author:
  Bobbala S ; Callery PS ; Coyle J ; Heenatigala Palliyage G ; Martin K ; Rojanasakul LW ; Rojanasakul Y ; Samart P
• Description:
  Objectives: A cure for cancer is out of reach for most patients due to chemoresistance. Cancer-associated fibroblasts (CAFs) play a vital role in cancer chemoresistance, but detailed understanding of the process particularly in chemoresistant lung cancer is lacking. In this study, we investigated programmed death-ligand 1 (PDL-1) as a potential biomarker for CAF-induced chemoresistance and evaluated its role and the underlying mechanisms of chemoresistance in non-small cell lung cancer (NSCLC). Materials and Methods: A systemic search of gene expression profiles of multiple tissues in NSCLC was carried out to determine the expression intensities of traditional fibroblast biomarkers and CAF-secreted protumorigenic cytokines. PDL-1 expression in CAFs was analyzed by ELISA, Western blotting, and flow cytometry. Human cytokine array was used to identify specific cytokines secreted from CAFs. Role of PDL-1 in NSCLC chemoresistance was assessed using CRISPR/Cas9 knockdown and various functional assays including MTT, cell invasion, sphere formation, and cell apoptosis. In vivo experiments were conducted using a co-implantation xenograft mouse model with live cell imaging and immunohistochemistry. Results: We demonstrated that chemotherapy-stimulated CAFs promoted tumorigenic and stem cell-like properties of NSCLC cells, which contribute to their chemoresistance. Subsequently, we revealed that PDL-1 expression is upregulated in chemotherapy-treated CAFs and is associated with poor prognosis. Silencing PDL-1 expression suppressed CAFs' ability to promote stem cell-like properties and invasiveness of lung cancer cells, favoring chemoresistance. Mechanistically, an upregulation of PDL-1 in chemotherapy-treated CAFs led to an increase in hepatocyte growth factor (HGF) secretion, which stimulates cancer progression, cell invasion, and stemness of lung cancer cells, while inhibiting apoptosis. Conclusion: Our results show that PDL-1-positive CAFs modulate stem cell-like properties of NSCLC cells by secreting elevated HGF, thereby promoting chemoresistance. Our finding supports PDL-1 in CAFs as a chemotherapy response biomarker and as a drug delivery and therapeutic target for chemoresistant NSCLC. [Description provided by NIOSH]
• Subjects:
  Biomarkers Lung Lung Diseases Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Author Keywords: Cancer-associated Fibroblasts CAFs Chemoresistance Chemotherapy Fibroblasts Gene Expression Hepatocyte Growth Factor HGF In Vivo Studies Lung Cancer Non-small Cell Lung Cancer NSCLC PDL-1 Programmed Death-ligand 1

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• ISSN:
  0169-5002
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  Ohio ; OSHA Region 3 ; OSHA Region 5 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  181
• NIOSHTIC Number:
  nn:20067710
• Citation:
  Lung Cancer 2023 Jul; 181:107258
• Contact Point Address:
  Yon Rojanasakul, Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA
• Email:
  yrojan@hsc.wvu.edu
• Federal Fiscal Year:
  2023
• Peer Reviewed:
  True
• Source Full Name:
  Lung Cancer
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:d25375f84b6a601e1ca99c6b68dae9d2681b0a0fd6afa5215fe77463973a0ee6fe5f4362fa5e0a38fa41d34335431282b9f6a562b912d4bd7458763cef6e883c
• Download URL:
  https://stacks.cdc.gov/view/cdc/229973/cdc_229973_DS1.pdf
• File Type:
  [PDF - 10.55 MB ]