A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response

David Wu; Ashley A. Hailer; Sijia Wang; Michelle Yuan; Jamie Chan; Abdullah El Kurdi; David Han; Hira Ali; Blaize D. Angio; Aaron Mayer; Maha Rahim; Ayano Kondo; Daniel M. Klufas; Esther A. Kim; A. Hunter Shain; Jaehyuk Choi; Tina Bhutani; Gregory L. Simpson; Roy C. Grekin; Roberto R. Ricardo-Gonzalez; Elizabeth Purdom; Jeffrey P. North; Jeffrey B. Cheng; Raymond J. Cho

doi:10.1126/sciimmunol.adi2848

A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response

David Wu, Ashley A. Hailer, Sijia Wang, Michelle Yuan, Jamie Chan, Abdullah El Kurdi, David Han, Hira Ali, Blaize D. Angio, Aaron Mayer, Maha Rahim, Ayano Kondo, Daniel M. Klufas, Esther A. Kim, A. Hunter Shain, Jaehyuk Choi, Tina Bhutani, Gregory L. Simpson, Roy C. Grekin, Roberto R. Ricardo-GonzalezElizabeth Purdom, Jeffrey P. North, Jeffrey B. Cheng^*, Raymond J. Cho^*

^*Corresponding author for this work

Dermatology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17–producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade–responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17–induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.

Original language	English (US)
Article number	adi2848
Journal	Science Immunology
Volume	9
Issue number	91
DOIs	https://doi.org/10.1126/sciimmunol.adi2848
State	Published - Jan 2024

Funding

Funding: this project was supported by grants from the leo Foundation to R.J.c., the national institute of arthritis and musculoskeletal and Skin Diseases (K08aR067243) to J.B.c., national institute of general medical Sciences (R01gm144493) to e.P., the tracy and guy Jacquier cScc Research Fund to a.h.S., and national cancer institute (R01ca265786) to a.h.S. this project was supported in part by funds from Sun Pharmaceutical industries to R.J.c. and J.B.c. Acknowledgments: We thank R. m. Sevey for visual representations of data and K. nam for hardware continuity. Funding: this project was supported by grants from the leo Foundation to R.J.c., the national institute of arthritis and musculoskeletal and Skin Diseases (K08aR067243) to J.B.c., national institute of general medical Sciences (R01gm144493) to e.P., the tracy and guy Jacquier cScc Research Fund to a.h.S., and national cancer institute (R01ca265786) to a.h.S. this project was supported in part by funds from Sun Pharmaceutical industries to R.J.c. and J.B.c. Author contributions: D.W., J.B.c., and R.J.c. conceptualized the study. D.W., e.P., a.h.S., a.a.h., J.P.n., R.J.c., and J.B.c. developed the methodologies. D.W., S.W., a.a.h., m.y., a.e.K., a.K., m.R., D.h., h.a., B.D., a.m., D.K., e.K., a.h.S., J. chan., t.B., g.S., J. choi, R.R.-g, R.c.g., J.P.n., J.B.c., and R.J.c. carried out the investigation. D.W. and R.J.c. performed visualization and constructed the figures. J.B.c. and R.J.c. obtained funding and provided administration for the study. e.P., R.J.c., and J.B.c. supervised the study. D.W., J.B.c., and R.J.c. wrote the original manuscript and also reviewed and edited the manuscript. Competing interests: J.B.c. and R.J.c. are investigators for Sun Pharmaceutical industries, leo Pharmaceuticals, Regeneron, Janssen, Bristol myers Squibb, and Sanofi (grants to their institution). the other authors declare that they have no competing interests. Data and materials availability: Bam files for samples are available at european genome archive egaS00001007373. Previously published sample Bam files available at european genome archive egaS00001005271. all analysis scripts are available at the online repository (https:// github.com/cho-cheng-lab/tildra). Processed data are published on Zenodo (https://zenodo. org/record/7834846). all coDeX imaging data are available on the enable medicine Platform at https://app.enablemedicine.com/portal/atlas-library/studies/7af6cda2-d6ed-41ed-a11c-094d9c40150b. Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contacts J.B.c. ([email protected]) or R.J.c. ([email protected]).

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1126/sciimmunol.adi2848

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Wu, D., Hailer, A. A., Wang, S., Yuan, M., Chan, J., Kurdi, A. E., Han, D., Ali, H., Angio, B. D., Mayer, A., Rahim, M., Kondo, A., Klufas, D. M., Kim, E. A., Hunter Shain, A., Choi, J., Bhutani, T., Simpson, G. L., Grekin, R. C., ... Cho, R. J. (2024). A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response. Science Immunology, 9(91), Article adi2848. https://doi.org/10.1126/sciimmunol.adi2848

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title = "A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response",

abstract = "Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17–producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade–responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17–induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.",

author = "David Wu and Hailer, {Ashley A.} and Sijia Wang and Michelle Yuan and Jamie Chan and Kurdi, {Abdullah El} and David Han and Hira Ali and Angio, {Blaize D.} and Aaron Mayer and Maha Rahim and Ayano Kondo and Klufas, {Daniel M.} and Kim, {Esther A.} and {Hunter Shain}, A. and Jaehyuk Choi and Tina Bhutani and Simpson, {Gregory L.} and Grekin, {Roy C.} and Ricardo-Gonzalez, {Roberto R.} and Elizabeth Purdom and North, {Jeffrey P.} and Cheng, {Jeffrey B.} and Cho, {Raymond J.}",

note = "Publisher Copyright: copyright {\textcopyright} 2024 the authors some rights.",

year = "2024",

month = jan,

doi = "10.1126/sciimmunol.adi2848",

language = "English (US)",

volume = "9",

journal = "Science Immunology",

issn = "2470-9468",

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Wu, D, Hailer, AA, Wang, S, Yuan, M, Chan, J, Kurdi, AE, Han, D, Ali, H, Angio, BD, Mayer, A, Rahim, M, Kondo, A, Klufas, DM, Kim, EA, Hunter Shain, A, Choi, J, Bhutani, T, Simpson, GL, Grekin, RC, Ricardo-Gonzalez, RR, Purdom, E, North, JP, Cheng, JB & Cho, RJ 2024, 'A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response', Science Immunology, vol. 9, no. 91, adi2848. https://doi.org/10.1126/sciimmunol.adi2848

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T1 - A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response

AU - Wu, David

AU - Hailer, Ashley A.

AU - Wang, Sijia

AU - Yuan, Michelle

AU - Chan, Jamie

AU - Kurdi, Abdullah El

AU - Han, David

AU - Ali, Hira

AU - Angio, Blaize D.

AU - Mayer, Aaron

AU - Rahim, Maha

AU - Kondo, Ayano

AU - Klufas, Daniel M.

AU - Kim, Esther A.

AU - Hunter Shain, A.

AU - Choi, Jaehyuk

AU - Bhutani, Tina

AU - Simpson, Gregory L.

AU - Grekin, Roy C.

AU - Ricardo-Gonzalez, Roberto R.

AU - Purdom, Elizabeth

AU - North, Jeffrey P.

AU - Cheng, Jeffrey B.

AU - Cho, Raymond J.

PY - 2024/1

Y1 - 2024/1

N2 - Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17–producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade–responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17–induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.

AB - Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of interleukin-23 (IL-23) signaling, but the genetic mechanisms underlying clinical responses remain poorly understood. Using single-cell transcriptomics, we profiled immune cells isolated from lesional psoriatic skin before and during IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was strongly attenuated. In contrast, poorly responsive patients were distinguished by persistent activation of IL-17–producing T (T17) cells, a mechanism distinct from alternative cytokine signaling or resistance isolated to epidermal keratinocytes. Even in IL-23 blockade–responsive patients, we detected a recurring set of recalcitrant, disease-specific transcriptional abnormalities. This irreversible immunological state may necessitate ongoing IL-23 inhibition. Spatial transcriptomic analyses also suggested that successful IL-23 blockade requires dampening of >90% of IL-17–induced response in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. Collectively, our data establish a patient-level paradigm for dissecting responses to immunomodulatory treatments.

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JF - Science Immunology

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M1 - adi2848

ER -

A single-cell atlas of IL-23 inhibition in cutaneous psoriasis distinguishes clinical response

Abstract

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