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  3. Chemotherapy-induced PDL-1 expression in cancer-associated fibroblasts promotes chemoresistance in NSCLC

Chemotherapy-induced PDL-1 expression in cancer-associated fibroblasts promotes chemoresistance in NSCLC

  • Lung Cancer. 2023 Jul;181:107258. doi: 10.1016/j.lungcan.2023.107258.
Gayathri Heenatigala Palliyage 1,  Parinya Samart 2,  Sharan Bobbala 1,  Liying W Rojanasakul 3,  Jayme Coyle 4,  Karen Martin 5,  Patrick S Callery 1,  Yon Rojanasakul 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA.
  • 2 Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA; Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
  • 3 Allergy and Clinical Immunology Branch, National Institute for Occupational Safety and Health, Morgantown, WV, USA.
  • 4 UES, Inc, Dayton, OH, USA.
  • 5 Department of Microbiology, Immunology & Cell Biology, West Virginia University, Morgantown, WV, USA; West Virginia University Cancer Institute, West Virginia University, Morgantown, WV, USA; Department of Research & Graduate Education, West Virginia University, Morgantown, WV, USA.
  • 6 Department of Pharmaceutical Sciences, West Virginia University, Morgantown, WV, USA; West Virginia University Cancer Institute, West Virginia University, Morgantown, WV, USA. Electronic address: yrojan@hsc.wvu.edu.
PMID: 37245409 DOI: 10.1016/j.lungcan.2023.107258
Abstract

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.

Keywords

Cancer-associated fibroblasts (CAFs); Chemoresistance; Hepatocyte growth factor (HGF); Non-small cell lung cancer (NSCLC); Programmed death-ligand 1 (PDL-1).

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