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

Jared Liu; Hsin-Wen Chang; Robby Grewal; Daniel D Cummins; Audrey Bui; Kristen M Beck; Sahil Sekhon; Di Yan; Zhi-Ming Huang; Timothy H Schmidt; Eric J Yang; Isabelle M Sanchez; Mio Nakamura; Shrishti Bhattarai; Quinn Thibodeaux; Richard Ahn; Mariela Pauli; Tina Bhutani; Michael D Rosenblum; Wilson Liao

doi:10.1016/j.xjidi.2021.100094

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

JID Innov. 2021 Dec 30;2(3):100094. doi: 10.1016/j.xjidi.2021.100094. eCollection 2022 May.

Authors

Jared Liu¹, Hsin-Wen Chang¹, Robby Grewal¹, Daniel D Cummins¹, Audrey Bui¹, Kristen M Beck², Sahil Sekhon³, Di Yan⁴, Zhi-Ming Huang¹, Timothy H Schmidt¹, Eric J Yang⁵, Isabelle M Sanchez⁶, Mio Nakamura⁷, Shrishti Bhattarai¹, Quinn Thibodeaux¹, Richard Ahn⁸, Mariela Pauli¹, Tina Bhutani¹, Michael D Rosenblum¹, Wilson Liao¹

Affiliations

¹ Department of Dermatology, University of California San Francisco, San Francisco, California, USA.
² Department of Dermatology, UT Southwestern Medical Center, Dallas, Texas, USA.
³ Department of Dermatology, Howard University, Washington, District of Columbia, USA.
⁴ The Ronald O. Perelman Department of Dermatology, NYU Grossman School of Medicine, NYU Langone Health, New York, New York, USA.
⁵ Department of Dermatology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
⁶ Department of Dermatology, College of Medicine, University of Illinois, Chicago, Illinois, USA.
⁷ Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁸ Institute for Quantitative & Computational Biosciences, University of California Los Angeles, Los Angeles, California, USA.

Abstract

The IL-17A inhibitor secukinumab is efficacious for the treatment of psoriasis. To better understand its mechanism of action, we investigated its impact on psoriatic lesions from 15 patients with moderate-to-severe plaque psoriasis undergoing secukinumab treatment. We characterized the longitudinal transcriptomic changes of whole lesional skin tissue as well as cutaneous CD4⁺ and CD8⁺ T effector cells and CD4⁺ T regulatory cells across 12 weeks of treatment. Secukinumab was clinically effective and reduced disease-associated overexpression of IL17A , IL17F, IL23A, IL23R, and IFNG in whole tissue as soon as 2 weeks after initiation of treatment. IL17A overexpression in T-cell subsets, primarily CD8⁺ T cells, was also reduced. Although secukinumab treatment resolved 89‒97% of psoriasis-associated expression differences in bulk tissue and T-cell subsets by week 12 of treatment, we observed expression differences involved in IFN signaling and metallothionein synthesis that remained unresolved at this time point as well as potential treatment-associated expression differences involved in IL-15 signaling. These changes were accompanied by shifts in broader immune cell composition on the basis of deconvolution of RNA-sequencing data. In conclusion, our study reveals several phenotypic and cellular changes within the lesion that underlie clinical improvement from secukinumab.

Keywords: CD8, CD8+ effector T cell; DE, differentially expressed; FDR, false discovery rate; PCA, principal component analysis; PGA, Physician’s Global Assessment; RNA-seq, RNA sequencing; Teff, effector T cell; Th, T helper; Treg, regulatory T cell.

Grants and funding

T32 AR007175/AR/NIAMS NIH HHS/United States