028 The activation status of nuclear factor κB in type 2 conventional dendritic cells before therapy correlates with clinical response to adalimumab

Abstract

Biologic therapies have revolutionised the treatment of psoriasis. Nevertheless, clinical response to therapy is unpredictable. Thus, there is a need to identify biomarkers predictive of response to enable patient stratification. Here, we investigate the effects of adalimumab (TNF-inhibitor) on the activation of nuclear factor κB (NF-κB) in the immune cells of psoriasis patients during the early phase of therapy. We hypothesize that monitoring the activation of the transcription factor downstream of the cytokine neutralized by a biologic can guide in the discovery of predictive biomarkers. Whole blood (n=16) and peripheral blood mononuclear cells (n=30) samples, obtained from psoriasis patients at baseline and weeks 1, 4 and 12 after commencing treatment, were stimulated with TNF or LPS; NF-κB nuclear translocation was quantified by imaging flow and NF-κB phosphorylation by phospho-flow cytometry. Clinical response was defined as 75% reduction in baseline psoriasis area severity index (PASI75) at week 12. TNF induced NF-κB translocation in T cells, dendritic cells (DCs), monocytes and neutrophils, while LPS, activated monocytes, DCs and neutrophils at baseline. In patients receiving adalimumab, TNF activation was significantly inhibited at each time point in T cells (92% at week 1, p<0.01), and to a lesser extent, in DCs (55% at week 1, p<0.05) compared to baseline but did not change in monocytes or neutrophils. As expected, adalimumab did not affect LPS-induced NF-κB translocation. However, we observed increased LPS-induced NF-κB translocation at baseline in the DC of patients who did not reach PASI75, as compared to patients reaching PASI75 (FDR<0.01). Importantly, this finding was replicated in an extended cohort of patients receiving adalimumab, where we detected increased LPS-induced NF-κB phosphorylation at baseline in type 2 conventional DC (cDC2) of patients not reaching PASI75 (FDR<0.001). Taken together, these data suggest that clinical response to adalimumab may depend on the baseline NF-κB activation status of cDC2.