Enhanced NF-\u03baB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis

Jonathan Barker ,Isabella Tosi ,Hira Bahadur Ale ,Michael R Barnes ,Rosa Andres-Ejarque ,Anna Chapman ,Nick Dand ,Debabrata Bandyopadhyay ,Jake Saklatvala ,Catherine Smith ,Nick J Reynolds ,Frank O Nestle ,Christopher E.m Griffiths ,Paola Di Meglio ,Katarzyna Grys ,Chrysanthi Ainali ,Shane Solanky ,Hemawtee Sreeneebus ,Zeynep Catak ,Emanuele De Rinaldis

doi:10.1038/s41467-021-25066-9

Abstract

Biologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. Here we perform in-depth immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. The heightened NF-κB activation is linked to increased DC maturation in vitro and frequency of IL-17+ T cells in the blood of non-responders before therapy. Moreover, lesional skin of non-responders contains higher numbers of dermal DC expressing the maturation marker CD83 and producing IL-23, and increased numbers of IL-17+ T cells. Finally, we identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome.

Highlights

Biologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response
Fresh whole blood, obtained at baseline before starting therapy and at week 1 (w1), 4 (w4) and 12 (w12) after the initiation of the treatment, was stimulated with either TNF or LPS or left unstimulated, and nuclear factor-κB (NF-κB) nuclear translocation was quantified as Rd score (Eq (1) see methods) in neutrophils, monocytes, dendritic cells (DC), natural killer (NK), NKT, CD4+ and CD8+ T cells (Fig. 1a and Supplementary Fig. 2)
In keeping with the results obtained in patients undergoing adalimumab therapy, TNF-induced NF-κB nuclear translocation was significantly inhibited by up to 98% in T, NK and NKT cells, but only partially in DC (70.48%, FDR = 0.084) with no effect on neutrophils and monocytes (Supplementary Fig. 3d)

Summary

Introduction

Biologic therapies have transformed the management of psoriasis, but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. We perform in-depth immunomonitoring of blood immune cells of 67 patients with psoriasis, before and during therapy with the anti-TNF drug adalimumab, to identify immune mediators of clinical response and evaluate their predictive value. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlates with lack of clinical response after 12 weeks of treatment. We identify and clinically validate LPS-induced NF-κBp65 phosphorylation before therapy as a predictive biomarker of non-response to adalimumab, with 100% sensitivity and 90.1% specificity in an independent cohort. Our study uncovers important molecular and cellular mediators underpinning adalimumab mechanisms of action in psoriasis and we propose a blood biomarker for predicting clinical outcome. 71% of patients with moderate-to-severe psoriasis achieved a 75% reduction in the standard objective disease severity score used in psoriasis—Psoriasis Area and Severity

Methods

Results

Conclusion