Transcriptomic Profiling of Plaque Psoriasis and Cutaneous T-Cell Subsets during Treatment with Secukinumab

Area of Science:

• Immunology
• Dermatology
• Genomics

Background:

• Psoriasis is a chronic inflammatory skin disease.
• Secukinumab, an interleukin-17A (IL-17A) inhibitor, is an effective treatment for psoriasis.
• Understanding secukinumab's mechanism of action at a molecular level is crucial.

Purpose of the Study:

• To investigate the longitudinal transcriptomic changes in psoriatic lesions and specific immune cells during secukinumab treatment.
• To elucidate the molecular mechanisms underlying secukinumab's clinical efficacy in psoriasis.

Main Methods:

• Analysis of whole lesional skin tissue and isolated CD4+ T effector, CD8+ T effector, and CD4+ regulatory T cells from 15 moderate-to-severe plaque psoriasis patients.
• Longitudinal transcriptomic profiling over 12 weeks of secukinumab treatment.
• RNA-sequencing data deconvolution to assess immune cell composition shifts.

Main Results:

• Secukinumab demonstrated clinical effectiveness, rapidly reducing overexpression of key psoriasis-associated genes (IL17A, IL17F, IL23A, IL23R, IFNG) within 2 weeks.
• Significant reduction in IL17A overexpression in T-cell subsets, particularly CD8+ T cells.
• While 89-97% of psoriasis-associated expression differences resolved by week 12, persistent differences in IFN signaling and metallothionein synthesis, along with potential IL-15 signaling alterations, were observed, alongside shifts in immune cell composition.

Conclusions:

• Secukinumab treatment leads to significant transcriptomic and cellular changes in psoriatic lesions, correlating with clinical improvement.
• The study identifies specific molecular pathways (IFN and IL-15 signaling) that may require further investigation regarding long-term treatment effects.
• These findings provide deeper insights into the multifaceted mechanism of action of IL-17A inhibition in psoriasis.