Mechanism, Consequences, and Therapeutic Targeting of Abnormal IL15 Signaling in Cutaneous T-cell Lymphoma

Abstract

Cutaneous T-cell lymphoma (CTCL) is the most common type of primary cutaneous lymphoma. Here we report that CTCL patients show increased interleukin-15 (IL-15) in a clinical stage-dependent manner. Mechanistically, we show that Zeb1 is a transcriptional repressor of IL-15 in T-cells and that hypermethylation of the Zeb1 binding region within the IL-15 promoter, as seen in CTCL patients, prevents Zeb1 binding and causes increased transcription of IL-15. Using a transgenic mouse model of IL-15, we provide evidence that overexpression of IL-15 induces a spontaneous CTCL that mimics the human neoplasm. Excessive autocrine production of IL-15 in T-cells inhibits an HDAC1-mediated negative autoregulatory loop, resulting in the upregulation of HDAC1 and HDAC6, and transcriptional induction of the onco-miR-21. Interruption of IL-15 downstream signaling with isotype-specific HDAC inhibitors halts (HDAC1) or significantly delays (HDAC6) the progression of CTCL in vivo and provides pre-clinical evidence supporting a hierarchical model of oncogenic signaling in CTCL.

Highly cytotoxic natural killer cells are associated with poor prognosis in patients with cutaneous T-cell lymphoma

“…19 There was significant upregulation of several IL-15 receptor subunits on NK cells ( Figure 2D). To further confirm activation of the IL-15 pathway, we evaluated STAT signaling in fresh peripheral blood NK cells by flow cytometry, because IL-15 signals through both STAT3 and STAT5.…”

“…19 Furthermore, IL-15 overexpression alone can induce CTCL in a murine model of the disease. 19 IL-15 is also known to stimulate NK-cell proliferation and cytotoxicity via phosphorylation of STAT5.…”

“…19,34,35 Indeed, as disease progresses, neoplastic CD4 1 T cells express higher levels of IL-15. 19 Furthermore, IL-15 overexpression alone can induce CTCL in a murine model of the disease. 19 IL-15 is also known to stimulate NK-cell proliferation and cytotoxicity via phosphorylation of STAT5.…”

“…19 IL-15 acts through a trimeric IL-15R complex to enhance NK-cell maturation and function. [20][21][22] Indeed, in a first-in-human phase 1 trial in patients with refractory solid cancer tumors, IL-15 treatment induced profound expansion of circulating NK cells (NCT01885897).…”

La mystérieuse œsophagite à éosinophiles garde encore quelques secrets

“…Cependant, l'IL-15 a été décrite aussi comme un facteur pro-Th2. Parexemple, un des gènes les plus expriméslors de l'expression transgénique d'IL-15 au niveau de l'épidermed es souris est GATA3, le facteur de transcription majeur de la lignéeT h2 [57]. Il aa ussi été montré que l'IL-15 pouvait induire la production des cytokines Th2 IL-5 et IL-13 par des cellules lymphoïdes associéesaux muqueuses [58], en synergie avecIL-18 qui nous l'avons vu plus haut est associée à l'EoE [46].…”