Linoleoyl-lysophosphatidylcholine suppresses immune-related adverse events due to immune checkpoint blockade.
Ian T MathewsPriyanka SaminathanMir HenglinMingyue LiuNamratha NadigCamille FangKysha MercaderSerena J CheeAllison M CampbellAbhijit A PatelSaumya TiwariJeramie D WatrousKarthik RameshMartina DickerKhoi DaoMelissa A MeyerPekka JousilahtiAki S HavulinnaTeemu NiiranenVeikko SalomaaLeo A B JoostenMihai G NeteaPan ZhengMitchell KronenbergSandip Pravin PatelJ Silvio GutkindChristian OttensmeierTao LongSusan M KaechCatherine C HedrickSusan ChengMohit JainSonia SharmaPublished in: medRxiv : the preprint server for health sciences (2024)
Immune related adverse events (irAEs) after immune checkpoint blockade (ICB) therapy occur in a significant proportion of cancer patients. To date, the circulating mediators of ICB-irAEs remain poorly understood. Using non-targeted mass spectrometry, here we identify the circulating bio-active lipid linoleoyl-lysophosphatidylcholine (LPC 18:2) as a modulator of ICB-irAEs. In three independent human studies of ICB treatment for solid tumor, loss of circulating LPC 18:2 preceded the development of severe irAEs across multiple organ systems. In both healthy humans and severe ICB-irAE patients, low LPC 18:2 was found to correlate with high blood neutrophilia. Reduced LPC 18:2 biosynthesis was confirmed in preclinical ICB-irAE models, and LPC 18:2 supplementation in vivo suppressed neutrophilia and tissue inflammation without impacting ICB anti-tumor response. Results indicate that circulating LPC 18:2 suppresses human ICB-irAEs, and LPC 18:2 supplementation may improve ICB outcomes by preventing severe inflammation while maintaining anti-tumor immunity.
Keyphrases
- endothelial cells
- mass spectrometry
- oxidative stress
- early onset
- end stage renal disease
- signaling pathway
- chronic kidney disease
- type diabetes
- stem cells
- high resolution
- ejection fraction
- induced pluripotent stem cells
- mesenchymal stem cells
- liquid chromatography
- cell therapy
- skeletal muscle
- weight loss
- patient reported outcomes