Malignant T cells induce skin barrier defects through cytokine-mediated JAK/STAT signaling in cutaneous T-cell lymphoma

• Published in: Blood Vol. 141; no. 2; pp. 180 - 193
• Main Authors: Gluud, Maria, Pallesen, Emil M. H., Buus, Terkild B., Gjerdrum, Lise Mette Rahbek, Lindahl, Lise M., Kamstrup, Maria R., Bzorek, Michael, Danielsen, Maria, Bech, Rikke, Monteiro, Madalena N., Blümel, Edda, Willerslev-Olsen, Andreas, Lykkebo-Valløe, Anders, Vadivel, Chella Krishna, Krejsgaard, Thorbjørn, Bonefeld, Charlotte Menne, Geisler, Carsten, Becker, Jürgen C., Koralov, Sergei B., Iversen, Lars, Litman, Thomas, Woetmann, Anders, Ødum, Niels
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.01.2023
• Subjects: Cytokines - metabolism; Filaggrin Proteins; Humans; Lymphoma, T-Cell, Cutaneous - pathology; Quality of Life; Skin Diseases - pathology; Skin Neoplasms - pathology; T-Lymphocytes - pathology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022016690

•Malignant T cells orchestrate changes in the microenvironment, which lead to skin barrier defects in cutaneous T-cell lymphoma.•We provide a novel rationale for JAK1 inhibition as an important adjuvant therapy for patients with cutaneous T-cell lymphoma. [Display omitted] 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. The clinical picture of cutaneous T-cell lymphoma (CTCL) is characterized by erythematous, eczematous, and papulosquamous skin changes, clinically and histologically similar to other inflammatory skin diseases. Gluud et al demonstrate that malignant T cells in CTCL secrete IL-13, IL-22, and oncostatin M to induce JAK-STAT signaling in surrounding keratinocytes, downregulating filaggrin expression, and impairing skin barrier function to promote inflammation. Blockade of these cytokines reverses these changes in human skin models and supports such therapeutic approaches in these diseases.