096 IL23-induced STAT3 Nuclear Translocation in MAIT Cells at Baseline is a Candidate Biomarker of Response to Biologics Targeting the IL23/IL17 Axis

The role of the interleukin (IL)23/IL17 axis in psoriasis is well-established and has led to the development of biologics targeting IL23 and IL17A. Ustekinumab, targets the IL12/23p40 shared subunit and blocks IL23-receptor interactions, restricting the activation of Signal Transducer and Activator of Transcription 3 (STAT3) in T cells, and IL17A production. Secukinumab blocks IL17A binding to its receptor, preventing keratinocyte activation. Although both biologics are effective, clinical response varies, highlighting the need to identify biomarkers predictive of response. To identify biomarkers of response to biologics targeting the IL23/IL17 axis, we first measured IL23-induced STAT3 translocation in peripheral blood mononuclear cells (PBMCs) of psoriasis patients (n=20) before (week (W)0) and during (W1, W4 and W12) ustekinumab therapy. Clinical response was assessed by 75% reduction in Psoriasis Area Severity Index (PASI75) at W12. STAT3 translocation in mucosal associated invariant T (MAIT) cells of PASI75 non-responders was significantly lower (p<0.05, FDR<0.05) than responders at W0 and highly predictive of PASI75 outcome in Receiver Operating Characteristic (ROC) curve analysis. Next, we measured STAT3 translocation in psoriasis patients prior to therapy with the anti-TNF adalimumab (n=10) or secukinumab (n=10). We observed no difference in STAT3 translocation between adalimumab PASI75 non-responders and responders. However, STAT3 translocation was significantly lower (p<0.05) in MAIT cells of secukinumab PASI75 non-responders compared to responders at W0. Ongoing work is aimed at refining this signal by deep-immunophenotyping of IL23-responsive cells of psoriasis patients undergoing biologic treatment. Taken together, we have identified IL23-induced STAT3 translocation in MAIT cells as a candidate biomarker predictive of response to biologics targeting the IL23/IL17 axis.