FC01 Higher IL-10+ T-cell and Treg-cell counts in psoriatic skin are associated with super-response to guselkumab: data from the Phase 3b GUIDE trial

Abstract Interleukin-10 (IL-10) and regulatory T (Treg) cells are immunosuppressive mediators with key roles in autoimmunity. Their increased presence is believed to counter-regulate pathogenic tissue-resident memory (TRM) and T-helper (Th)17 cells in psoriasis. The ongoing randomized, double-blinded, controlled Phase 3b GUIDE trial (NCTO3818035) examines the clinical and immunological impact of an extended guselkumab [an interleukin (IL)-23p19 subunit inhibitor] dosing interval in patients with moderate-to-severe plaque-type psoriasis. Patients who achieved a psoriasis area and severity index (PASI) = 0 at both Week [W]20 and W28 with guselkumab treatment were defined as super-responders (SRes). In this mechanistic substudy of GUIDE, we aimed to determine whether SRes show immunological differences in skin T-cell composition vs. non-SRes, using flow cytometry analysis of non-lesional (at W0) and lesional (at W0, W4, W28 and W68) skin cells taken from 63 patients. At ­baseline, IL-10+ T-cell counts were higher in both non-lesional and lesional skin of SRes vs. non-SRes (with an SRe to non-SRe ratio of 3.1:1 in non-lesional skin, and a 3.0:1 ratio in lesional skin; P < 0.05). This trend was maintained in lesional skin after treatment with guselkumab, with higher IL-10+ T-cell counts observed in SRes than non-SRes at W4 (with an SRe to non-SRe ratio of 4.6:1; P < 0.05) and at W28 (with a ratio of 4.4:1; P < 0.05). Treg-cell (CD4+CD25+FoxP3+) counts were also higher in SRes at W4 and W28 (with an SRe to non-SRe ratio of 3.1:1 at W4, and a ratio of 2.9:1 at W28; P < 0.05). Further analysis of effector T-cell subsets showed that CD8+ TRM and IL-17A+ T-cell counts in lesional skin were reduced by guselkumab up to W68. Normalization of these T-cell populations in lesional skin to non-lesional skin levels appeared to be earlier in SRes (W28) compared with non-SRes (W68). These findings from GUIDE suggest that clinical super-response to guselkumab may be characterized by higher IL-10+ T-cell and Treg-cell counts, and faster normalization of CD8+ TRM and IL-17A+ T-cell counts. Therefore, higher IL-10+ T-cell and Treg-cell counts may act as predictive biomarkers for a better response to guselkumab in patients with moderate-to-severe plaque-type psoriasis.