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

Abstract

Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterised by accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms hampering the quality of life and are entry sites for bacterial infection - a major cause of morbidity and mortality in advanced disease. What drives the pathological processes that compromise the skin barrier remains unknown. Here, we report on increased transepidermal water loss and compromised expression of 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 IL-13, IL-22 and Oncostatin M) that activate STAT3 signalling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, repression of filaggrins could be counteracted by a cocktail of antibodies targeting these cytokines/receptors, by siRNA-mediated knockdown of JAK1/STAT3, and by JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, Tofacitinib, increases filaggrin expression in lesional skin from mycosis fungoides patients. Taken together, these findings indicate that malignant T cells secrete cytokines, which induce skin barrier defects through 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 CTCL patients with advanced disease and a compromised skin barrier.

New JAK3-INSL3 Fusion Transcript—An Oncogenic Event in Cutaneous T-Cell Lymphoma

“…Aberrant JAK3 activation and its downstream signaling pathways are implicated in the pathogenesis of CTCL, and inhibition of JAK3 has been a therapeutic strategy for CTCL with increasing attentions. Many studies have shown that JAK3 inhibitors had good effects in CTCL cell lines [15,41,42]. For example, Tofacitinib, a JAK3 selective inhibitor, showed inhibitory effects on intracellular growth factor and cytokine-mediated signals.…”

CDK9 recruits HUWE1 E3 ligase to degrade RARα in a kinase independent manner and offers therapeutic opportunities for cutaneous T-cell lymphoma

“…Numerous single-cell RNA sequencing (scRNA-seq) literatures have demonstrated prominent heterogeneity of CTCL cancer cells, both in lesional skin (patch/plaque/tumor) and circulation [30][31][32][33][34][35][36][37] . To decipher the CDK9 expression across different malignant T cell clusters, we analyzed 3 publicly available scRNA-seq datasets containing lesional skin or blood samples from patients with MF mycosis fungoides (MF) or Sézary syndrome (SS) as well as healthy controls 32,34,38 .…”

Severe relapses of cutaneous T‐cell lymphoma after treatment of chronic graft‐versus‐host disease with ruxolitinib

“…The JAK/STAT pathway has been found activated in various T-cell lymphomas. 7 Notably, CTCL can exhibit somatic JAK mutations contributing to the dysregulation of JAK/ STAT signaling 8,9 Therefore, this pathway is considered as a novel target for CTCL therapy using specific JAK inhibitors. However, in a phase 2 trial evaluating ruxolitinib in various subtypes of refractory T-cell lymphomas, one only out of 7 MF patients showed a partial response lasting over 18 months.…”