Identification of PDL1 Drivers in Models of Head and Neck Squamous Cell Carcinoma by Genome Wide Screening
Year: 2020
Type: dissertation
Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and as only approximately 50% of patients survive five years after diagnosis, new treatment options are urgently needed. A complex array of molecular and microenvironmental alterations are believed to play a role in HNSCC pathogenesis, including suppression of antitumor immunity by expression of the immune checkpoint signal Programmed Death Ligand 1 (PDL1). The advancement of predictive and prognostic biomarkers, as well as rationally designed and personalized treatment regimens, will be especially crucial to improving outcomes across the spectrum of HNSCC subtypes. In an effort to comprehensively understand disease heterogeneity and mechanisms regulating immune escape, we have profiled various genetic, transcriptomic, and immunologic features of HNSCC. The focus of this work was on the regulation of PDL1, a target for immunotherapy that has garnered significant attention in recent years. We aimed to provide a more complete portrait of the molecular pathways contributing to immunosuppression in HNSCC, and to identify signals that could be exploited as biomarkers and therapeutic targets. We utilized multiple genome wide screening techniques to select HNSCC cells with altered PDL1 expression and validated several hits nominated by these screens, most notably FGFR and TLR2 signaling. We expect these findings to contribute to a broader understanding of PDL1 checkpoint regulation in models and tumors with diverse genetic and phenotypic characteristics, and that this knowledge will ultimately lead to novel biomarkers and therapeutic combinations to improve patient outcomes.
Author: Jacqueline E. Mann
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3042789785