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.

MJMvE: none. MMvdW: none. HBK: none. NMMD: none. MS: none. RJV: none. FDMvS: none. BO: none. SN: none. KPMS: Consulting/advisory relationship: Abbvie, Sairopa. Research funding: TigaTx, Bristol Myers Squibb, Philips, Genmab, Pierre Fabre. Honoraria: Bristol Myers Squibb. All paid to institution. FW: has advisory relationships with Janssen and Takeda, and received research funding from Takeda, Galapagos, BMS, Sanofi, and Leo Pharma.

This investigator-initiated study received funding from Bristol Myers Squibb (grant number CA209-6JY), paid to institution.

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The biobank review committee of the University Medical Center Utrecht gave ethical approval for this work (Biobank protocol TC-bio 18-123 and Material release protocol TC-bio 23-200).

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All data produced in the present study are available upon reasonable request to the authors, to the extent permitted by applicable law.