The Effect of AhR Agonist Tapinarof on Dendritic Cells and T cells In Vitro

Abstract

Psoriasis is a chronic inflammatory skin condition mediated by a dysregulated immune system. Patients with psoriasis not only deal with plaques on their skin, they also have an increased risk of developing comorbidities such as obesity, cardiovascular disease, and metabolic syndromes. Current treatments most commonly involve topical corticosteroids for mild disease; however, these treatments do not always work and stopping treatment normally leads to relapse. For more severe cases, physicians often prescribe biologics such as secukinumab and etanercept that target important cytokines (IL-17A and TNFa, respectively) involved in disease pathogenesis and maintenance. While these treatments can be highly effective, long term systemic immunosuppression impacts the ability to fight off infections and other diseases. Additionally, halting treatment can lead to relapse. Tapinarof is a new non-steroidal topical treatment for atopic dermatitis and psoriasis that shows promising clinical trial results with long-lasting effects. While not yet FDA-approved, phase 3 clinical trials showed complete or near-complete lesion resolution in 35-40% of patients with a long remission of 4 months on average after discontinuation. Recent studies have pinned tapinarof as an aryl hydrocarbon receptor (AhR) agonist, a first-in-its-class therapeutic. Due to the novelty of this treatment and the complex behavior of AhR, the mechanism behind tapinarof has yet to be elucidated. Our in vitro studies examined how the drug directly affects important mediators of psoriasis such as dendritic cells and T cells. We investigated tapinarof’s effect on dendritic cell development and maturation as well as T cell exhaustion, cytokine production, resident memory T cell generation/survival, and the transition from regulatory T cells to Th17. Our results indicated that tapinarof inhibits formation, cytokine production and persistence of resident memory T cells as well as upregulates immunosuppressive marker CD39 in vitro.