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Linoleoyl-lysophosphatidylcholine suppresses immune-related adverse events due to immune checkpoint blockade.

medRxiv : the preprint server for health sciences

Authors: Ian T Mathews, Priyanka Saminathan, Mir Henglin, Mingyue Liu, Namratha Nadig, Camille Fang, Kysha Mercader, Serena J Chee, Allison M Campbell, Abhijit A Patel, Saumya Tiwari, Jeramie D Watrous, Karthik Ramesh, Martina Dicker, Khoi Dao, Melissa A Meyer, Pekka Jousilahti, Aki S Havulinna, Teemu Niiranen, Veikko Salomaa, Leo A B Joosten, Mihai G Netea, Pan Zheng, Mitchell Kronenberg, Sandip Pravin Patel, J Silvio Gutkind, Christian Ottensmeier, Tao Long, Susan M Kaech, Catherine C Hedrick, Susan Cheng, Mohit Jain, Sonia Sharma

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 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.

PMID: 39148854

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