Selective BET inhibition as potential hidradenitis suppurativa treatment

Summary: Abstract Body: Bromodomain and extraterminal (BET) proteins regulate immune-related gene expression. Here we assessed the effects of a 3rd generation BET inhibitor (DC-9476, DC) on the Hidradenitis suppurativa (HS) phenotype in vitro and ex vivo. Treatment of PBMCs from 3 healthy donors (HD) and 3 HS patients with DC (0.03-3µM) for 24h decreased CCL2, GM-CSF and TNF-α secretion in all groups. DC also lowered CD8+ T-cell numbers in HS PBMCs but did not affect CD4+ T-cells, monocytes and B-cells. Ex vivo analysis of nodule- or fistula-containing lesional skin vs peri-lesional skin from 3 HS patients showed increased MKI67 expression in nodule-lesional skin (qRT-PCR), enhanced cytokine expression (IL1B, CXCL8) and/or secretion (CXCL8, IL-17A, IL-6) in both lesion types, and higher CCL20 expression in nodules, confirming abnormal keratinocyte proliferation and a complex HS cytokine profile. DC treatment (300nM, 1µM) robustly lowered MIK67 expression in all skin types, while it reduced IL-17A secretion in fistula-containing skin, downregulated CCL20 expression in peri-lesional and nodule-containing skin, and decreased CXCL8 expression and CXCL8 secretion in nodule-containing skin in 2 out of 3 donors. To assess T cell activation and recruitment, hair follicles (HFs) from 1 HD were stimulated with a HS-relevant cytokine cocktail (TNF-α, IL-17A, IL-1β) and co-cultured with autologous PBMCs. HFs and/or PBMCs were treated with vehicle or DC (300nM, 1µM). Cytokine stimulation caused intrafollicular PBMC infiltration, which was reduced by HF treatment with 300nM DC, while PBMC treatment with 1µM DC reduced CXCL8 secretion from HFs. In summary, these in vitro and ex vivo data demonstrate the potential of DC to ameliorate early HS responses but further pre-clinical studies are needed to refine treatment strategies and identify responsive patients. Alizée Le Riche¹, Janina Nienhaus¹, Mi-Jeong Kim², Michal Segal-Salto², Sylke Schneider-Burrus³, Falk Bechara⁴, Hanieh Erdmann⁵, Luca Rastelli², Janin Edelkamp¹, Marta Bertolini¹ 1. QIMA Life Sciences, QIMA Monasterium, Münster, Germany. 2. DeepCure Inc, Boston, MA, United States. 3. Havelklinik GmbH & Co KG, Berlin, Germany. 4. St. Josef Hospital, Bochum, Germany. 5. Praxis Dr. Pajouh, Bargteheide, Germany. Translational Studies: Cell and Molecular Biology