Differential Changes in Inflammatory Mononuclear Phagocyte and T-Cell Profiles within Psoriatic Skin during Treatment with Guselkumab vs. Secukinumab

Cellular sources of IL-23 and IL-17A driving skin inflammation in psoriasis remain unclear. Using high-dimensional unsupervised flow cytometry analysis, mononuclear phagocytes T cells were examined the same lesions patients before during guselkumab (IL-23p19 blocker) or secukinumab (IL-17A treatment. Among CD11c+HLA-DR+ phagocytes, CD64brightCD163−CD14brightCD1c−CD1a‒ inflammatory monocyte‒like predominant IL-23–producing and, together with CD64−CD163−CD14−IL-23p19−TNF-α+ dendritic cell‒like cells, increased lesional compared those nonlesional taken from patient. Within CD8+CD49a+ and/or CD103+ tissue-resident memory CD4+CD25+FoxP3+ regulatory CD4+CD49a−CD103− increased. Moreover, relatively rare CD8+ equally contributed to production. Both treatments decreased frequencies monocyte‒like, cell‒like, cells. In contrast, reduced while maintaining vice versa for secukinumab. Neither drug modified IL-17A+IL‒17F+/– CD4+ This study reveals identity major IL-23+ phagocyte IL-17+ T-cell subsets psoriatic paves way a better understanding mode action drugs targeting IL-23/IL-17A pathway psoriasis. Plaque is debilitating immune-inflammatory disease affecting 1–3% individuals western countries (Lowes et al., 2014Lowes M.A. Suárez-Fariñas M. Krueger J.G. Immunology psoriasis.Annu Rev Immunol. 2014; 32: 227-255Crossref PubMed Scopus (886) Google Scholar). keratinocytes immune contribute pathogenesis (Albanesi 2018Albanesi C. Madonna S. Gisondi P. Girolomoni G. The interplay between psoriasis.Front 2018; 9: 1549Crossref (159) Therapies that target through blockade show high clinical efficacy psoriasis, providing compelling evidence IL-23/IL-17 key driver (Blauvelt 2017Blauvelt A. Papp K.A. Griffiths C.E. Randazzo B. Wasfi Y. 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Mitsui al.A subpopulation CD163-positive classically activated 2010; 130: 2412-2422Abstract (197) Given role IL-17 cytokines play deeper characterization MNP types producing warranted. directly isolated patient biopsies, we report cellular phenotypic data generated small substudy 1,048-patient multicenter Evaluate Comparative Efficacy CNTO 1959 (Guselkumab) Secukinumab Treatment Moderate Severe Plaque-type Psoriasis (ECLIPSE) trial (Reich We composition (L) (NL); identified IL-23, IL-17A, TNF-α; evaluated modulation lesion sampled at baseline start change proportion among CD45+ (Supplementary Figure S1a). percentage was significantly L relative NL S1b). subdivided their CD64 CD163 (Figure 1a), respectively (Chapuy 2019Chapuy Bsat Sarkizova Rubio Therrien Wassef al.Two distinct colonic CD14+ single-cell RNA profiling Crohn’s disease.Mucosal 12: 703-719Crossref (28) skin, CD64brightCD163‒ CD64+CD163+ unchanged, whereas CD64−CD163‒ decreased. A large CD14bright S1c, left panel). No difference CD14 observed right CD64bright CD64− segregated according CD1c CD1a examine contribution each subset 1b c). CD64brightCD163‒CD1c−CD1a− (Infl Mo‒like) CD64−CD163−CD1c−CD1a− DC‒like DC‒like) largely innate infiltrate. CD64‒CD163‒CD1c+CD1a+ separated into CD1c+CD1adim CD1c+CD1abright subsets. cDC2 LCs represented 1c). frequency CD3+ S1d). As 1d, infiltrate predominantly due (gated non-CD8+ because CD4 surface staining downregulated phorbol 12-myristate 13-acetate; Supplementary S1e) FoxP3+CD25+ (Tregs). time. Because expressed S1f), TRMs CD49a 1e f) CD49a−CD103− largest population plaques. There but significant increase CD8+CD49a+CD103− CD8+CD49a+CD103+ direct CD8+CD49a−CD103− lesions. Collectively, CD64brightCD163−CD1c−CD1a− Infl Mo‒like analyses proinflammatory cytokine profiles IL-17A+ IL-17F+ augmented lesions, patients, IL-22+ 2a). By percentages CD3+TNF-α+ decreased, IFN-γ+ remained stable. Cytokine Tregs low followed similar trend S2a). All IL-17A+CD8+ 2b). For highest IL-17A–expressing IL-17F paralleled S2b). TNF-α+ only S2c). Multiple IL-17F, IFN-γ, TNF-α, IL-22 cytokine‒coexpressing both S2d). When total approximately 30% 2c). phenotype, profile, proliferation status next using PhenoGraph (Levine 2015Levine J.H. Simonds E.F. Bendall Davis K.L. Amir elel-AD. Tadmor M.D. al.Data-driven dissection AML progenitor-like correlate prognosis.Cell. 162: 184-197Abstract (598) Four IL-17A‒enriched clusters visualized concatenated t-Distributed Stochastic Neighbor Embedding plot 2d S3a). (T_1) IL-17A+IL-17F+ (T_2) (T_3) (T_4) clusters. four Ki-67− coexpressed IFN-γ. separate panel revealed CD8+CD103+ CD4+CD103− PD-1+ CD40L+ 2e). PD-1 (mean fluorescence index) higher IL-17A+CD8+CD103+ when IL-17A+CD4+CD103− S3b). reverse CD40L expression. IL-17A− CD4+- CD8+-enriched unchanged S3c). clusters, (T_11) TRM, (T_12), (T_9) IFN-γ+TNF-α+Ki-67+ (T_8) TNF-α only. Furthermore, CD4+FoxP3+ one cluster (T_5) best CD25bright another (T_6) CD25dim 2f). Although it has been reported distribution adaptive varies across body (Del Duca 2019Del Pavel A.B. Dubin Song Wallace E.B. Peng X. al.Major differences pathways different sites individuals.J 139: 2228-2232.e10Abstract (13) FoxP3+ not influenced site biopsy S4a). Overall, expressing IL-23p19+CD11c+HLA-DR+ increased, 3a). Analysis IL-23p19+ indicated CD64brightCD163− 70% 3b), this 3c). CD64−CD163− (10%) (20%) collectively frequency. To gain insight phenotype IL-23–expressing applied dimensionality reduction Expression feature plots showed enriched islands coincided mostly CD1cbright, CD1abright, CD207bright regions 3d). One overlapped CD163bright area. Unsupervised 3e). CD64brightCD163−CD14brightHLA‒DRdim CD1c−CD1a− FcεRIα− MNP_1 Mo‒like_1) MNP_2 Mo‒like_2) being IL-23p19+TNF-α− negative cytokines. remaining HLA-DRdim MNP_3 MNP_4 Mϕ‒like populations; CD14brightIL-23p19loTNF-α− (Mϕ_1) CD14dimIL-23p19‒TNF-α‒ (Mϕ_2) Three CD64dim/− TNF-α. MNP_5 (cDC2_1) tended ∼65% MNP_6 (cDC2_2) These CD64dim/−CD163dim/−CD14dim/−HLA-DRbrightCD1cbright/+CD1a+/brightCD207dimFcεRIα+ cDC2_1 coexpressing IL-23p19. MNP_7 elevated CD64−CD163−CD14−HLA-DRbrightCD1c−CD1a−CD207−FcεRIα+ only, resembling Finally, MNP_8 CD64−CD163−CD14−HLA-DRdimCD1c+CD1abrightCD207brightFcεRIα− IL-23p19 consistent LCs. seen proportions S4b). Thus, CD64brightCD163−CD14brightHLA-DRdimCD1c−CD1a−CD207dim did impact cohort PASI score groups treated yield viable recovered suspensions weeks 4 24 S5a b). assessed time points 4). baseline, markedly week 4a). reflected groups. seemed plateau no 24, secukinumab, 24. reflect present 4b). IL-23– TNF-α–expressing (TNFα− (TNFα+ cDC2_1) levels 4c). IL-23p19− groups, secukinumab-treated Altogether, resulted IL-23p19+TNFα− IL-23p19−TNFα+ IL-23p19+TNFα+ 5a). decrease guselkumab-treated 5a S6). CD49a+CD103+/− depicted 5b, comparable group, group. Interestingly, 5c). differential ratio Tregs/CD8+CD49a+CD103+ S6b driven CD4+CD25brightFoxP3+ T_5 CD4+CD25dimFoxP3+ T_6 Treg 5d). At point, patients. relationship positively correlated drug-treated S7). IL-17A–producing irrespective 5e). led TRMs, strongly Tregs. However, IL-17A– IL-17F–producing drug. recent head-to-head had faster onset maintenance over ECLIPSE pharmacodynamic effects players CD64brightCD163‒CD14brightCD1c‒CD1a− responsible most production, CD64−CD163−CD14−CD1c−CD1a− 4. compartment, all they exerted effect 4, TRMs. Conversely, S8). Tregs-to-CD8+ related superior long-term control 48. Two caveats interpretation earlier endpoint (week 24) immunophenotyping number samples analyzed believed contributors (Szabo (Gallais 2019Gallais Hoffer Ignatov Zitti Ehrström skewed pool triggers psoriasis-associated responses never-lesional 143: 1444-1454Abstract Höllbache