Distinct roles of Lysophosphatidylcholine in modulating neutrophil viability, inflammation and function 4040

Abstract Description Immune Checkpoint Blockade therapy advances solid tumor treatment, but a major challenge is immune-related adverse events (ICB-irAEs), which can lead to treatment discontinuation. Neutrophils, as key cellular mediators of systemic immunity, play a central role in both the initiation and resolution of inflammation across various diseases. Recent studies highlight excessive and prolonged blood neutrophilia as an indicator of severe ICB-irAEs. Our research identifies a protective mechanism involving the lipid Lysophosphatidylcholine (LPC), which suppresses ICB-irAEs. In patients treated with ipilimumab (anti-CTLA4) or pembrolizumab (anti-PD1) for melanoma, lung cancer, or other tumors, lower LPC levels correlated with severe ICB-irAEs and increased neutrophilia. In murine models of ICB-colitis and DSS-colitis, supplementation of unsaturated LPC specifically suppressed colonic inflammation and reduced neutrophilia in the blood and tissues. Here we explore cell-intrinsic effects of LPC supplementation on mature human peripheral neutrophils. We present evidence that saturated and unsaturated LPC differentially modulate neutrophil viability, activity, and inflammatory functions. While saturated LPC stimulated pro-inflammatory responses in mature human neutrophils, unsaturated LPC promoted immunologically silent neutrophil apoptosis. Our results suggest that unsaturated LPC may specifically mitigate severe ICB-related irAEs by dampening neutrophil-driven inflammation. Funding Sources Supported by : NCI R01 - 1R01CA256133-01A1 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)