ABSTRACT: Background/Objectives: Immune-related cutaneous adverse events (ircAE) are common complications of cancer immunotherapy and provide insight into immune-related ad-verse events (irAE) more broadly. To enhance our molecular understanding, we char-acterized ircAE resulting from single-agent (PD1) and combined immunotherapy reg-imens (P+C). Clinically, maculopapular rashes (MPR) and toxic epidermal necrolysis (TEN) resemble ircAE, providing a valuable basis for investigations. Methods: To in-vestigate the transcriptome and immune infiltrates in ircAE, we conducted transcriptomic analyses and multiplexed immunohistochemistry on skin biopsies from patients re-ceiving PD1 and P+C, as well as those with MPR, TEN, and healthy controls. Results: Principal component analysis revealed distinct transcriptomic clustering between ircAE, MPR, and TEN. Specifically, PD1 ircAE exhibited a gene expression profile similar to TEN, with upregulation of Type-I-response-related genes (e.g., CXCL9 Log2FC 5.34, p<0.0001, CXCL10 Log2FC 6.03, p<0.0001), while P+C ircAE more closely resembled MPR. Immune infiltrates differed significantly between all groups (p=0.002 by PER-MANOVA for all groups). CD4 T-cells were abundant in the dermis of ircAE from any type of immunotherapy. However, PD1 stained positive in 1.07% of CD4 cells with PD1 monotherapy, compared to 0.3%, 0.4%, and 0.08% in P+C, MPR, and TEN, respectively. Conclusions: This study identified distinct molecular and cellular signatures in ircAE depending on the type of immune checkpoint blockade. aPD1-associated ircAE share similarities with the cytotoxic profile of TEN, while P+C more closely mirrored MPR. These findings support the need for tailored management strategies for ircAE, emphasizing personalized therapeutic approaches to minimize treatment interruptions while preserving the efficacy of cancer immunotherapy.
