Therapeutic insights from spatial mapping of hidradenitis suppurativa skin lesions at single cell resolution

Summary: Abstract Body: Hidradenitis Suppurativa (HS) is a debilitating inflammatory skin disease characterized by abscesses and purulent draining sinus tracts. Effective treatments remain elusive, underscoring the need for deeper mechanistic understanding. Using 45-antibody CODEX immunofluorescence imaging, flow cytometry, and Xenium spatial transcriptomics, we generated a spatial atlas of cell types in HS lesions at single-cell resolution. Our CODEX analysis demonstrated increased densities of B cells, plasma cells (PCs), neutrophils, CD4 T, and CD8 T cells in HS lesions compared with control skin (p < 0.001). These immune infiltrates often formed tertiary lymphoid structures (TLS) and bona fide germinal center reactions. PCs were a dominant immune population in lesional skin; we estimated PC numbers in lesions of a severe HS patient were similar to the PC numbers found in all lymphoid organs of a healthy adult. TLS were increased in more severe disease, and PC densities correlated strongly with TLS densities (r=0.69; p=2.6e-10), suggesting TLS may generate PCs in situ. PCs were not reduced in HS lesions from TNF inhibitor-treated versus biologic-naïve patients. This may explain the limited efficacy of TNF inhibitors, and highlights PCs as potential therapeutic targets. CODEX analyses further revealed heterogeneity in sinus tracts in HS lesions; only 40% of tracts were surrounded by dense immune infiltrates. Spatial transcriptional profiling of HS lesions identified IL-36γ as specifically expressed in keratinocytes of inflammatory tracts compared with non-inflammatory tracts (p<0.01), with undetectable expression elsewhere in the dermis. This finding explains why Phase 2 clinical trials targeting IL36R with spesolimab reduced draining sinus tracts but not abscesses or nodules. Together, our findings advance our understanding of HS pathogenesis and highlight PCs and the IL-36 pathway as therapeutic targets in HS. Victoria Fang¹, Matthew Lee¹, Abigail Zellmer², Hua Huang¹, Naomi Douek¹, Laura Cesar¹, Michelle Weir¹, Alaina Hunt¹, Donna Brennan-Crispi¹, Derek Oldridge², E. John Wherry¹ 1. University of Pennsylvania, Philadelphia, PA, United States. 2. The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, United States. Adaptive and Auto-Immunity