Comprehensive characterization of the inflammatory ecosystems in immunotherapy-induced adverse events versus chronic...

Immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) share symptomatic and therapeutic similarities with chronic inflammatory diseases (CIDs). However, the molecular distinctions between irAEs and CIDs remain unclear. Herein, we systematically compared irAEs and CIDs across multiple tissues using large-scale multi-omics profiling.

We compiled a transcriptomic compendium of over 4.3 million cells from 1137 samples and 24 spatial transcriptomes across diverse inflammatory sites in irAEs and CIDs. In addition, we collected 526 pre-ICI and post-ICI treatment-matched blood transcriptomes coupled with germline exomes, alongside 75 serum proteomes with irAE information.

Hallmark gene signatures and cell states that characterize the inflammatory milieu of various irAEs and CIDs were defined. Across tissues, irAEs involve a distinct inflammatory ecosystem enriched with myeloid-derived components, including NLRP3 ⁺ mononuclear phagocytes, LAMP3 ⁺ dendritic cells, and CXCL8/10 cytokine signaling, alongside TNFRSF18 ⁺ regulatory T cell, T/natural killer interferon, and HAVCR2 ⁺ exhausted T cell. These cell states exhibit unique interaction patterns, forming spatially localized niches specific to irAEs but absent in CIDs. Severe irAEs are accompanied by elevated CXCL10 cytokine signaling post-ICI treatment, with a higher prevalence among HLA-B*46:01 carriers.

Our multimodal analyses highlight key differences between irAEs and CIDs, indicating that irAEs constitute a distinct inflammatory ecosystem that differentiates them from CIDs. Our study provides insights into potential biomarkers and therapeutic targets for improved irAE management.