Enhanced NF-κB signaling in type-2 dendritic cells at baseline predicts non-response to adalimumab in psoriasis [article]

Rosa Andres Ejarque, Hira Bahadur Ale, Katarzyna Grys, Isabella Tosi, Shane Solanky, Chrysanthi Ainali, Zeynep Catak, Hemawtee Sreeneebus, Jake Saklatvala, Nick Dand, Emanuele de Rinaldis, Anna Chapman (+9 others)
2020 medRxiv   pre-print
Biological therapies have transformed the management of psoriasis but clinical outcome is variable leaving an unmet clinical need for predictive biomarkers of response. To identify the immune determinants of response to the anti-TNF drug adalimumab and evaluate their predictive value, we performed in-depth immunomonitoring of blood immune cells of 67 psoriasis patients, before and during therapy. We assessed proximal TNF signaling events, by measuring NF-κB nuclear translocation and
more » ... ion, and downstream effects, such as cell phenotype and function. Enhanced NF-κBp65 phosphorylation, induced by TNF and LPS in type-2 dendritic cells (DC) before therapy, significantly correlated with lack of clinical response after 12 weeks' treatment. The heightened NF-κB activation was mechanistically 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 contained more activated dermal DC and increased numbers of IL-17+T cells. Finally, we identified and clinically validated 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 key molecular and cellular players underpinning adalimumab mechanisms of action in psoriasis and proposes a blood biomarker for predicting clinical outcome.
doi:10.1101/2020.11.09.20228502 fatcat:amhyptgwjfbsxhn6hb6zvd2lc4