Author ORCID Identifier

https://orcid.org/0000-0001-8607-2520

Semester

Summer

Date of Graduation

2023

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Yon Rojanasakul

Committee Member

Sharan Bobbala

Committee Member

Liying W. Rojanasakul

Committee Member

Jayme Coyle

Committee Member

Karen H. Martin

Committee Member

Patrick S. Callery

Abstract

A cure for cancer is out of reach for most patients due to chemoresistance. Cancer-associated fibroblasts (CAFs), one of the most abundant types of stromal cells in the tumor microenvironment, are known to provide functional and structural support for tumor progression. These cells also play a role in cancer chemoresistance, but a 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 underlying mechanisms of chemoresistance in non-small cell lung cancer (NSCLC). We demonstrated that chemotherapy-stimulated CAFs promoted tumorigenic and stem cell-like properties of NSCLC cells, which could 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. We uncovered that an upregulation of PDL-1 led to an increase in hepatocyte growth factor (HGF) secretion from chemotherapy-treated CAFs, which stimulates cancer progression, cell invasion, and stemness of lung cancer cells, while inhibiting apoptosis. Taken together, 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.

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