Biologic drugs, such as ustekinumab, have significantly transformed psoriasis treatment. Ustekinumab targets the shared interleukin (IL)-12/23p40 subunit, preventing IL-23 from binding to its receptor and blocking translocation of Signal Transducer and Activator of Transcription 3 (STAT3). Although ustekinumab is highly effective, clinical response is variable and there is an unmet need for the identification of biomarkers predictive of response. Here we monitor IL-23-induced STAT3 activation in peripheral blood mononuclear cells (PBMCs) to identify predictive biomarkers of outcome to ustekinumab. We established an imaging flow cytometry assay to quantify STAT3 nuclear translocation (RD Score), in healthy donors (n=4) and identified CD8+ mucosal-associated invariant T (MAIT) cells (RD=0.53±0.07) and CCR6+CD161+Vα7.2- CD8+ T cells (RD=0.6±0.08) to be highly responsive to IL-23. Next, we assessed STAT3 translocation within PBMCs of psoriasis patients, recruited by the Psoriasis Stratification to Optimise Relevant Therapy (PSORT) consortium, before ustekinumab therapy (baseline) and at week (W)1, W4 and W12 of therapy. Clinical response was assessed applying a binary model, using 75% reduction in baseline Psoriasis Area Severity Index (PASI75), or a continuous model, where the outcome is % residual disease at W12. We found a statistically significant reduction in IL-23-induced STAT3 translocation in CD8+ MAIT cells of PASI75 non-responders (n=8) compared to responders (n=7) at baseline (RD=0.34±0.03 vs 0.47±0.07, p<0.05, FDR<0.05). Additionally, IL-23-induced STAT3 translocation in MAIT cells at baseline correlated with residual disease at W12 (P=0.02, R2=0.34). Taken together, we have established an immune monitoring assay for biomarker discovery in the context of anti-IL-23 biologics and have identified a promising predictive biomarker of outcome to ustekinumab which warrants replication and further validation.

ESDR051 - STAT3 nuclear translocation in circulating MAIT cells is a potential biomarker of clinical outcome to ustekinumab in psoriasis

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING