Agonism of VISTA immune checkpoint as a potential treatment therapy for hidradenitis suppurativa

Summary: Abstract Body: Hidradenitis Suppurativa (HS) is a chronic follicular occlusion disease marked by persistent inflammation, scarring, and tunnel formation. New evidence implicates immune checkpoints, notably the V-domain Ig-containing suppressor of T cell activation (VISTA), in HS etiology. Nanostring DSP GeoMx transcriptomic analysis shows elevated VISTA in CD8 region of HS tissues when compared to ruptured follicular cysts (RFC), a histologic mimicker that spontaneously resolves. The GeoMx proteomic panels confirm heightened VISTA and T cell activation markers (LAG3, GITR, ICOS) in CD8+ regions of HS, while multiplex immunofluorescence reveals a threefold increase in VISTA+ cells. Notably, VISTA-positivity correlates negatively with its inhibitory ligand IGSF11 across HS samples, suggesting that decreased agonistic signaling to VISTA may contribute to unchecked, chronic inflammation in HS. We developed a novel in vitro explant system to evaluate VISTA agonists as potential therapeutics, using interleukin-6 (IL6) as a readout because it strongly correlates with HS severity in clinical setting. Triamcinolone served as a positive control by reducing IL6 levels in all samples. Notably, in a patient sample where the patient had been injected with triamcinolone one week prior to excision, IL6 levels were similarly reduced but returned to baseline when the sample was placed in our control medium. Baloxavir, recently identified as a VISTA agonist, also significantly decreased IL6 in our explant system, suggesting a role for VISTA-mediated inflammation control. Given the absence of established HS mouse models, this ex vivo platform is an essential tool for screening targeted therapies and lays the groundwork for future VISTA-based treatments for HS. Michal Kidacki¹, Christina Cho², Anjali Jaiswal¹, Francesc Lopez-Giraldez³, Rachel Breidbart¹, William Damsky¹, Henry Hsia⁴, Anna Eisenstein¹, Matthew D. Vesely¹, Lieping Chen^{2, 1, 5} 1. Dermatology, Yale University, New Haven, CT, United States. 2. Immunobiology, Yale University, New Haven, CT, United States. 3. Yale Center for Genome Analysis, Yale University, New Haven, CT, United States. 4. Plastic Surgery, Yale University School of Medicine, New Haven, CT, United States. 5. Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, United States. Translational Studies: Preclinical