Serum proteomic profiling of patients with immune checkpoint inhibitor-associated eczematous dermatitis highlights therapeutic targets and immunologic distinctions from atopic dermatitis

Summary: Abstract Body: The use of immune checkpoint inhibitors (ICIs) to treat cancer leads to dermatologic side effects known as cutaneous immune-related adverse events (cirAEs) in up to 60% of patients. Despite their substantial impact on quality of life, no standardized treatment protocol exists for the various cirAE phenotypes, and, to our knowledge, the proteomic profiles of cirAEs have not yet been characterized. To better understand the pathophysiology underlying cirAEs, serum samples were collected from 4 patients with ICI-induced eczematous reactions (ICI-Ecz) and 11 patients with atopic dermatitis (AD), the hallmark eczematous dermatitis, matched on age, race, and sex. Proteomic data for 393 proteins were extracted using the OLINK Proximity Extension Assay and analyzed using R software and Bioconductor packages. Differential expression was defined as |fold change|>1.4 and false discovery rate<0.1. Compared to AD patients, ICI-Ecz patients displayed positive Th1-skewing, with increased expression of IL2-RA, TNF-R1, TNF-R2, IL-1RT1, and IL-1RT2. Many proteins in the Th17 immune pathway (IL-17RA, IL-6RA, PI3/elafin) were also upregulated in ICI-Ecz serum. Moreover, pathway analysis performed by Gene Set Variation Analysis (GSVA) exhibited significant upregulation of Th1 and Th17 pathways (p<0.05), the former of which is known to play a key role in anti-tumor immunity. There were no significant differences in GSVA scores for the Th2 and JAK/STAT pathways, indicating similar overall expressions of these common therapeutic targets in ICI-Ecz and AD. These preliminary results demonstrate immunologic distinctions between eczematous cirAEs and AD, as well as offer insight into the insufficiently studied pathophysiology of cirAEs. This understanding is critical to clinicians’ ability to successfully treat cirAEs while maintaining the anti-tumor efficacy of ICIs. Benjamin D. Hu¹, Jacob Glickman¹, Camille Powers¹, Digpal Gour¹, Jimin Woo-Pennacchio¹, Yeriel Estrada¹, Emma Guttman-Yassky¹, Nicholas Gulati¹ 1. Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States. Translational Studies: Preclinical