Taming toxicity: LISA’s path to better management of immune related Adverse Events (irAEs) 3390

Abstract Description Immunotherapy has transformed cancer therapy, but emergence of immune-related adverse events (irAEs) remains a major challenge. Serious irAEs can lead to cessation of treatment & fatal toxicities. There remains limited mechanistic understanding of irAEs due to an absence of reliable preclinical models. To address this, we developed the Lifestyle Induced Susceptibility to irAEs (LISA) mouse model. LISA integrates dietary & microbiome modifications, utilizing a Western Diet (WD) rich in fats & simple sugars, which reshapes the microbiome and drives clinically relevant irAEs within the skin, gastrointestinal tract, & liver. irAE severity correlates with host factors such as sex, age, treatment modality (anti-PD1 vs. combination therapy), and duration of dietary exposure. scRNAseq and flow cytometry analyses revealed an upregulation of cycling CD8+ T cells & unstable CD4+ Tregs expressing inflammatory markers (T-bet, TNFα, IFNγ). Unstable Tregs were specific for microbial and dietary antigens, and both factors were required for Treg dysfunction and irAE development. Finally, we found that lifestyle intervention could prevent both Treg dysfunction and irAE symptoms. The LISA model offers a novel and effective tool for studying irAEs, mirroring key clinical features of adverse events. It provides valuable insights into the immune mechanisms underlying irAE severity and susceptibility, with potential to inform new therapeutic strategies for managing immunotherapy-related toxicities. Funding Sources Supported by NIH New Innovators Award (DP2 Mechanism); The Pittsburgh Foundation Award; Damon Runyon Award to A.E.O.D. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)