Differential Immune Checkpoint Protein Expression in HNSCC: The Role of HGF/MET Signaling

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint inhibitors targeting PD1/PD-L1 show promise but have limited efficacy in a subset of head and neck squamous cell carcinoma (HNSCC) patients.
• Non-responding HNSCC tumors may possess alternative immune checkpoints that could be therapeutically targeted.
• Hepatocyte Growth Factor (HGF) and its receptor MET signaling pathways are implicated in cancer progression and immune evasion.

Purpose of the Study:

• To investigate the expression profile of various immune checkpoint ligands on HNSCC tumor cell lines.
• To determine the impact of HGF/MET signaling on the expression of these checkpoint ligands.
• To identify potential alternative immune targets in HNSCC that do not respond to PD1/PD-L1 blockade.

Main Methods:

• Utilized mRNA sequencing to identify checkpoint ligand expression in six HNSCC cell lines.
• Employed antibody-based techniques for validation and quantification of checkpoint ligand expression.
• Assessed the effect of HGF stimulation on checkpoint ligand levels in HNSCC cell lines.

Main Results:

• VISTA exhibited the highest and most ubiquitous RNA expression among the investigated checkpoint ligands in HNSCC cell lines.
• PD-L2 and B7-H3 showed lower and variable expression across cell lines, while B7-H4 was detected only in the Detroit 562 cell line.
• HGF stimulation enhanced PD-L2 expression but decreased other checkpoint ligands, notably B7-H4, suggesting a complex regulatory role.

Conclusions:

• VISTA represents a highly expressed and broadly distributed immune checkpoint ligand in HNSCC.
• HGF signaling differentially modulates immune checkpoint ligand expression in HNSCC, with implications for therapeutic resistance.
• The interplay between HGF/MET signaling and checkpoint ligands like B7-H4 warrants further investigation, particularly concerning its link to epithelial-mesenchymal transition.