Linoleoyl-lysophosphatidylcholine suppresses immune-related adverse events due to immune checkpoint blockade
Mathews, I. T.; Saminathan, P.; Henglin, M.; Liu, M.; Nadig, N.; Fang, C.; Mercader, K.; Chee, S. J.; Campbell, A. M.; Patel, A. A.; Tiwari, S.; Watrous, J. D.; Ramesh, K.; Dicker, M.; Dao, K.; Meyer, M. A.; Jousilahti, P.; Havulinna, A. S.; Niiranen, T.; Salomaa, V.; Joosten, L. A.; Netea, M. G.; Zheng, P.; Kronenberg, M.; Patel, S. P.; Gutkind, J. S.; Ottensmeier, C.; Long, T.; Kaech, S. M.; Hedrick, C. C.; Cheng, S.; Jain, M.; Sharma, S.
Show abstract
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.
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