Genome-wide open reading frame profiling identifies fibroblast growth factor signaling as a driver of PD-L1 expression in head and neck squamous cell carcinoma.

Abstract

Head and neck squamous cell carcinomas (HNSCC) are associated with significant treatment-related morbidity and poor disease-free and disease-specific survival, especially in the recurrent and metastatic (R/M HNSCC) setting. Inhibition of the programmed death-1/ligand-1 (PD-1/PD-L1) immune checkpoint is accepted as a first-line treatment strategy for R/M HNSCC and has expanded into the neoadjuvant, definitive, and adjuvant settings. To understand cellular signals modulating the PD-L1 in HNSCC, we profiled a HNSCC cell-line with a genome-wide open reading frame (ORF) library of 17,000 individual constructs (14,000 unique genes). We identified 335 ORFs enriched in PD-L1high cells and independently validated five of these ORFs (FGF6, IL17A, CD300C, KLR1C and NFKBIA) as drivers of PD-L1 upregulation. We showed that exogenous FGF ligand is sufficient to induce PD-L1 expression in multiple HNSCC cell lines and human immature dendritic cells. Accordingly, overexpression of FGFR1, FGFR3 or the FGFR3 S249C and D786N mutants common to HNSCC tumors also induced PD-L1 overexpression on tumor cells. Small molecule inhibition of FGF signaling abrogated PD-L1 upregulation in these models and also blocked "classical" IFNγ-regulated PD-L1 expression in a STAT1-independent manner. Finally, we found that FGF specifically upregulated a glycosylated form of PD-L1 in our study, and exogenous FGF led to concomitant upregulation of glycosyltransferases that may stabilize PD-L1 on the surface of HNSCC cells. Taken together, our study supports a potential role for FGF/FGFR pathway signaling as a mechanism driving immune escape and rationalizes further exploration of novel combination therapies to improve clinical responses to PD-1/PD-L1 axis inhibition in HNSCC.

• Authors: Jacqueline E Mann, Joshua D Smith, Aditi Kulkarni, Susan K Foltin, Erin B Scheftz, Isabel R Murray, Elizabeth Gensterblum-Miller, Collin V Brummel, Apurva Bhangale, Rebecca C Hoesli, J Chad Brenner
• Journal: Oral oncology (Oral Oncol) Vol. 146 Pg. 106562 (11 2023) ISSN: 1879-0593 [Electronic] England
• PMID: 37666053 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• Antigens, Surface
• B7-H1 Antigen
• CD300C protein, human
• Fibroblast Growth Factors
• Ligands
• Membrane Glycoproteins
• Programmed Cell Death 1 Receptor
• FGFR1 protein, human
• FGFR3 protein, human

Topics

• Humans
• Antigens, Surface
• B7-H1 Antigen (metabolism)
• Fibroblast Growth Factors (genetics)
• Head and Neck Neoplasms (genetics)
• Ligands
• Membrane Glycoproteins (genetics)
• Open Reading Frames
• Programmed Cell Death 1 Receptor
• Squamous Cell Carcinoma of Head and Neck (genetics)