International Psoriasis Council

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Advancing Knowledge. Improving Care.

Commentary: Single-cell and Spatial Transcriptomics Analysis of Psoriasis Skin Lesions After IL-23 Inhibition

Commentary -Tiago Torres

Tiago Torres, MD, PhD

Centro Hospitalar Universitário do Porto, University of Porto

Porto, Portugal

Bio

PUBLICATIONS

Single-cell Analysis of Psoriasis Resolution Demonstrates an Inflammatory Fibroblast State Targeted by IL-23 Blockade. Francis L, McCluskey D, Ganier C, et al. Nat Commun. 2024 Jan 30;15(1):913. doi: 10.1038/s41467-024-44994-w.

A Single-cell Atlas of IL-23 Inhibition in Cutaneous Psoriasis Distinguishes Clinical Response. Wu D, Hailer AA, Wang S, et al. Sci Immunol. 2024 Jan 26;9(91):eadi2848.  doi: 10.1126/sciimmunol.adi2848. 

Why this article was chosen

Biologic therapies targeting the IL-23/IL-17 axis have proven highly effective in psoriasis. However, the precise molecular basis underlying clinical responses and the drug’s mechanism of action remains poorly understood. Longitudinal single-cell and spatial transcriptomics analysis of psoriasis skin lesions, before and during targeted biologic therapy, can elucidate early mechanisms of drug action as well as the genetic mechanisms underlying clinical responses.

Commentary

In the past decade, developing several highly effective biologic agents targeting the interleukin (IL)-23/IL-17 axis has revolutionized the treatment of moderate to severe plaque psoriasis. Despite their clinical trial efficacy, 10 to 20% of the patients treated with these drugs fail to achieve an acceptable clinical response. These drugs’ early mechanisms of action remain poorly understood, as well as the genetic mechanisms underlying clinical responses, particularly in those who respond suboptimal to these therapies.

The authors used single-cell and spatial transcriptomics analysis of psoriasis skin lesions before and during IL-23 blockade in these two studies. They aimed to understand the early events underlying the effects of IL-23 inhibition (using risankizumab) and the precise molecular basis underlying clinical responses to this therapeutic class (using tildrakizumab).

Francis et al. investigated the early effects of risankizumab in resolving psoriasis, targeting the first two weeks of treatment. Using single-cell analysis, psoriatic skin was profiled at baseline, day three, and day 14 of treatment. It was observed that there was a marked downregulation of IL-17 signaling in keratinocytes, fibroblasts, and vascular endothelial cells sampled after 14 days of risankizumab treatment, with a modest impact on interferon-gamma (IFN-γ) activity. Notably, fibroblast and myeloid populations displayed the most extensive genetic changes starting on day three. Moreover, a pro-inflammatory WNT5A+/IL24+ fibroblast state was identified, showing a marked upregulation of tumor necrosis factor (TNF) and IL-17 signaling, which largely declined after three days of IL-23 inhibition (also detected in other psoriasis datasets, in patients receiving other systemic and topical therapeutics). Together, this indicates that restoring this cell state is crucial for resolving psoriatic inflammation. WNT5A and IL24 promote keratinocyte proliferation and cytokine release, suggesting inflammatory crosstalk between WNT5A+/IL24+ fibroblasts and keratinocytes. Spatial transcriptomic data further validated this by mapping WNT5A+/IL24+ fibroblasts to the upper dermis in proximity to keratinocytes.

This data provides significant comprehension of the early mechanisms of action of IL-23 inhibitors, highlighting that the evolution of inflammatory fibroblast states is a crucial feature of resolving psoriasis skin.

On the other hand, Wu et al. used longitudinal single-cell and spatial transcriptomics analysis of psoriasis skin lesions to evaluate the genetic mechanisms underlying clinical response to another IL-23 inhibitor, tildrakizumab.

In patients responding strongly to IL-23 blockade, there was a down-regulation of IL-17 signaling due to reduced abundance but not the proportion of T17 cells in psoriatic lesions. Cytokines like IL-17A, IL-17F, and IL-26 were downregulated as expected for an upstream blockade. However, although the absolute numbers of T17 cells were also reduced, their proportionate cellular abundance was not. Also, a subset of general inflammatory transcripts was decreased, probably due to feedback loops with other cell types, such as antigen-presenting cells.

Interestingly, a subset of IL-23 blockade-responsive patients had abnormal T-cell signatures. These residual disease-specific transcriptional abnormalities may be responsible for triggering recurrence and preventing durable remissions, which may need ongoing IL-23 inhibition. Finally, poorly responsive patients were distinguished by persistent activation of IL-17-producing T cells, a mechanism probably responsible for the persistence of pathologic keratinocyte responses to IL-17, although at diminished levels. In contrast, the strong IL-23 responders nearly abolished this keratinocyte signal. Nevertheless, the spatial transcriptomic analyses suggested that successful IL-23 blockade required more than 90% reduction of IL-17-induced response in lymphocyte-adjacent keratinocytes, which may be considered a substantially high threshold.

Although these molecular assays are still far from being implemented in our clinical practice, these data allow us to better understand the mechanism of action of IL-23 inhibitors. It also correlates the clinical and molecular response in patients treated with these therapies to help distinguish causes of therapy resistance and, probably in the future, to personalize treatments.

One thought on “Commentary: Single-cell and Spatial Transcriptomics Analysis of Psoriasis Skin Lesions After IL-23 Inhibition

  1. Luis Puig says:

    Great and insightful comment on groundbreaking research. One is left to wonder to what extent one skin biopsy is representative of the overal/topographic activity of the disease, and which could be the drivers of differential response. Much work remains to be done in truly refractory locations and morphologic variants, e.g. palmoplantar pustular psoriasis, with T2 response admixture!

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