Bio-active lipids protect against immune-related adverse events due to immune checkpoint blockade therapy

Abstract Introduction: Immune checkpoint blockade (ICB) therapy has been revolutionary in its ability to treat advanced malignancies. Yet many patients receiving ICB develop related adverse events (IRAEs), a leading cause for discontinue treatment. Analyzing who IRAEs can help advance our knowledge of the molecular drivers these poorly understood off target toxicities. Methods: Our recent study plasma from undergoing ipilimumab (anti-CTLA4) or pembrolizumab (anti-PD1) melanoma, lung cancer other solid tumors was assessed using high-resolution liquid chromatography-tandem mass spectrometry. Results: We uncovered novel protective mechanism class circulating bio-active lipids that suppress ICB-related IRAEs. Significant reduction circulation associated with increased ICB-mediated Mouse-models (both DSS-colitis and humanized models) were used show supplementation ameliorated colonic inflammation without impacting ICB-driven tumor regression. also significant correlation between increasing neutrophil counts decreased bioactive circulation. Conclusion: These results uncover previously unidentified regulatory whereby identified specifically deleterious during therapy, while preserving anti-tumor immunity, suggesting be developed as new therapeutic strategy improve clinical outcomes immunotherapy. Supported by grants NIH (R01CA256133-02)