Immune-related cutaneous adverse events display distinct clinical and molecular characteristics, depending on immune checkpoints targeted
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. Overall design: Retrospective study, consisting of a comparative analysis of samples from patients developing immune-related cutaneous adverse events following aPD1-based and aCTLA4/aPD1, as well as samples from healthy skin comparators, maculopapular drug rash and toxic epidermal necrolysis