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

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 contribute to more targeted irAE management regimens. We took a multi-omics approach to identify blood- and tissue-based predictors of steroid response and to explore underlying mechanisms of steroid non-response in irAEs. In the blood, steroid non-response correlated with trends for elevated Tc1/Tc17 CD8 ⁺ T cells and serum interleukin (IL)-17, IL-6, IL-12 and IL-23 prior to initiation of steroids, along with persistent (CD8 ⁺ ) T cell proliferation and activation after start of steroids. A remarkably fast decrease in inflammatory gene signatures and lymphocyte infiltration was observed in colitis tissue of steroid responders obtained within 24h after initiation of steroids. Peripheral T cell PD-1 receptor occupancy was not associated with steroid response. Colitis tissue of steroid non-responders was enriched for activated CD4 ⁺ memory T cells and a pronounced type 1/17 immune response. Together, our findings suggest rapid immunological effects of steroids in circulating cells and irAE-affected tissue and support that an enhanced type 1/type 17 response is associated with steroid non-response in irAEs.