Blood and tissue correlates of steroid non-response in checkpoint inhibition-induced immune-related adverse events

Background: High-dose steroids constitute the cornerstone of first-line treatment for immune-related adverse events (irAEs) associated with immune checkpoint inhibitors, but compromise antitumor immunity. A deeper understanding of irAEs and their response to steroids can improve management. Methods: Using a multi-omics approach, we investigated blood- and tissue-based correlates of steroid response, focusing on gastro-intestinal irAEs, in the largest cohort to date. Results: Here we show clear trends for elevated T_C1/T_C17 CD8⁺ T cells and Th1/Th7-associated interleukins before steroid initiation, and persistent (CD8⁺) T cell activation after initiation of steroids in blood of steroid non-responders. Cross-sectional analysis of colitis tissue suggested lower lymphocyte infiltration within 24 h in steroid responders. Peripheral T cell PD-1 receptor occupancy was unrelated to steroid response. Non-responders’ colitis tissue was enriched with activated CD4⁺ memory T cells and a pronounced type 1/17 immune response. Conclusions: These findings highlight rapid steroid effects on circulating cells and irAE-affected tissue and support that an enhanced type 1/type 17 response may be associated with steroid non-response in irAEs. Validation of these findings in larger cohorts is warranted.