Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma
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Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA–mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Blood |
| Vol/bind | 141 |
| Udgave nummer | 2 |
| Sider (fra-til) | 180-193 |
| Antal sider | 14 |
| ISSN | 0006-4971 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:
K. Rindler, P. M. Brunner, X. Song and P.-L. Chen graciously assisted in the annotation and elaboration of their respective single-cell RNA sequencing data sets. This research was funded by grants from the LEO Foundation through the LEO Foundation Skin Immunology Research Center and LEO Foundation Grant (LF-OC-20-000351) (S.B.K.), The Danish Cancer Society (Kræftens Bekæmpelse), the Fight Cancer Program (Knæk Cancer), Novo Nordisk Research Foundation, Novo Nordisk Foundation Tandem Program (grant NNF21OC0066950), Lundbeck Foundation (A.W.-O.), and The Danish Council for Independent Research (Danmarks Frie Forskningsfond, 2 project grants [N.Ø.]; Sapera Aude Talent Grant [DFF-4092-00122] [T.K.]). LINAK A/S, Nordborg, Denmark. The funding source had no influence on the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Contribution: M.G. and N.Ø. conceived and designed the study and drafted the manuscript; N.Ø. obtained the funding and supervised the study; E.M.H.P. T.B.B. L.M.R.G. L.M.L. M.B. M.D. R.B. C.K.V. A.L.-V. M.R.K. S.B.K. L.I. T.L. and A.W. provided administrative, technical, or material support; and all authors performed acquisition, analysis, or interpretation of data and critical revision of the manuscript for important intellectual content.
Funding Information:
This research was funded by grants from the LEO Foundation through the LEO Foundation Skin Immunology Research Center and LEO Foundation Grant ( LF-OC-20-000351 ) (S.B.K.), The Danish Cancer Society (Kræftens Bekæmpelse), the Fight Cancer Program (Knæk Cancer), Novo Nordisk Research Foundation , Novo Nordisk Foundation Tandem Program (grant NNF21OC0066950 ), Lundbeck Foundation (A.W.-O.), and The Danish Council for Independent Research (Danmarks Frie Forskningsfond, 2 project grants [N.Ø.]; Sapera Aude Talent Grant [ DFF-4092-00122 ] [T.K.]). LINAK A/S, Nordborg, Denmark.
Publisher Copyright:
© 2023 The American Society of Hematology
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