Nevus-epidermal interactions in halo nevus highlight the role of apoptosis in disease pathogenesis

Summary: Abstract Body: Vitiligo, an autoimmune depigmentation disorder driven by CXCR3+ CD8+ T cells recruited by keratinocyte-secreted CXCL9/10 chemokines, remains elusive due to the scarce active lesions and surviving melanocytes. Halo nevus shares phenotypic and pathogenic similarities with vitiligo, offers an alternative model to identify therapeutic targets applicable to both. We aimed to elucidate halo nevus pathogenesis via spatial transcriptomics profiling of nevus and epidermal cells as a vitiligo model. Analysis of 5 pediatric halo nevi and 6 melanocytic nevi controls revealed CXCL9 upregulation in both nevus and epidermal cells. Nevus cells showed increased MHC class I/II genes (HLA-A/B/C, HLA-DPA1), IFNγ-induced genes (IFITM1, IFI27) and oxidative stress genes (SOD2), with enriched pathways in IFNγ response, JAK-STAT3 signaling, and apoptosis. Keratinocytes exhibited stress, apoptosis and immune response with upregulated FOS, HSPB8, MHC class I genes (HLA-B/C) and IFNγ response genes (GBP2, TRIM11). Pathways including MYC/E2F targets, oxidative phosphorylation and MTORC1 signaling were downregulated, reflecting dysfunctional cell growth and metabolism. Cell-cell interaction analysis revealed VEGFC-KDR ligand-receptor pair downregulation, suggesting nevus cell apoptosis, while TNFSF10-TNFRSF10B upregulation suggested keratinocyte apoptosis via FADD and caspases. Keratinocyte death may impair melanocyte homeostasis, increasing apoptotic susceptibility. We propose keratinocyte apoptosis contributes to pathogenesis by releasing melanocyte antigens, facilitating dendritic cell cross-presentation and activating melanocyte-specific immune cells. These findings establish a novel link between keratinocyte apoptosis and autoimmune initiation, highlighting keratinocytes' role in disease progression. Chong Won Choi*¹, Yookyung S. Chun*², Ji Hwan Moon⁴, Yun-Hui Jeon², Hyun Jung Kwon¹, Seon-Pil Jin†³ 1. Dermatology, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea (the Republic of). 2. Seoul National University Graduate School Department of Biomedical Science, Seoul, Seoul, Korea (the Republic of). 3. Dermatology, Seoul National University Hospital, Jongno-gu, Seoul, Korea (the Republic of). 4. Samsung Medical Center Samsung Genome Institute, Gangnam-gu, Seoul, Korea (the Republic of). Pigmentation, Melanoma, and Melanoma Immune Surveillance