Clinical Report: The Influence of Zapnometinib and Influenza A Virus on the HLA Class I Ligandome in Human Lung Adenocarcinoma Cells

Overview

This study investigates the effects of zapnometinib, a MEK inhibitor, on the HLA-I ligandome in human lung adenocarcinoma cells infected with Influenza A virus. Findings indicate that while zapnometinib and IAV infection do not significantly alter HLA-I surface expression, they induce notable changes in the peptide presentation and immune recognition pathways.

Background

Influenza viruses present a significant global health challenge, with limited antiviral options due to resistance. Host-directed therapies, such as MEK inhibitors, offer a promising alternative by targeting viral replication and modulating immune responses. Understanding the impact of these therapies on antigen presentation is crucial for developing effective antiviral strategies.

Data Highlights

No significant changes in HLA-I surface expression were observed (fold changes 1.01-1.13, p > 0.05). Immunopeptidomics revealed 3–12% changes in HLA-I-presented peptides and 3–14% modulation of defined ligand subsets (log2 fold change ≥ 2, adjusted p < 0.05).

Key Findings

• Zapnometinib treatment did not significantly alter HLA-I surface expression in lung adenocarcinoma cells.
• Immunopeptidomic analysis showed allotype-specific changes in HLA-I-presented peptides.
• Condition-specific enrichment in cellular pathways was observed, particularly in interferon-induced pathways.
• Zapnometinib selectively modulated antiviral responses and cell cycle pathways without consistent reduction in HLA-I levels.
• Ligandome remodeling after IAV infection affected key antiviral hubs, while zapnometinib did not show significant effects on these hubs.

Clinical Implications

The findings suggest that zapnometinib may serve as a host-directed antiviral strategy, enhancing immune recognition without compromising overall HLA-I expression. This dual action could be beneficial in treating influenza infections, particularly in patients with limited antiviral options.

Conclusion

Zapnometinib demonstrates potential as a therapeutic agent in modulating immune responses against influenza A virus while maintaining HLA-I expression levels. Further research is warranted to explore its role in antiviral therapy.

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