Immune Function Abnormalities in Peripheral Blood Mononuclear Cell Cytokine Expression Differentiates Stages of Cutaneous T-Cell Lymphoma/Mycosis Fungoides

Abstract

Purpose: Mycosis fungoides (MF) is a cutaneous T-cell lymphoma (CTCL) characterized by neoplastic skin-homing T cells. To better understand the immunopathogenesis of MF, we analyzed the functional ability of peripheral blood mononuclear cells (PBMC) from early and late MF/CTCL patients to express cytokine genes. In late stage MF/CTCL, patients were separated into those with blood involvement (+B) and without blood involvement (−B). Experimental Design: We analyzed TH1 (interleukin 2 (IL-2), IFN-γ), TH2 (IL-4, IL-5, IL-10, IL-13), and TH17 (IL-17) cytokine gene expression from activated PBMCs from normal (n = 12), psoriasis (n = 6), early MF/CTCL (n = 11), and late MF/CTCL+B (n = 4) and MF/CTCL−B (n = 3) by quantitative real-time PCR. Results: PBMCs from early MF/CTCL and psoriasis showed higher induction of IL-2, IL-4, and IFN-γ genes than those from normal and late MF/CTCL−B and MF/CTCL+B (P < 0.05) in descending order. PBMCs from late MF/CTCL−B exhibited generally the highest level of IL-5, IL-10, IL-13, and IL-17 expression compared with the other groups. PBMCs from early MF/CTCL and late MF/CTCL−B had similarly elevated IL-13 and IL-17. Of all groups, PBMCs from late MF/CTCL+B had the lowest levels of IL-2 (P < 0.05), IL-4, IFN-γ, IL-13, and IL-17. Conclusions: The different pattern of cytokine gene expression suggests a change in immune function in MF/CTCL from early MF/CTCL to late MF/CTCL−B to late MF/CTCL+B. These stages are consistent with localized disease associated with an anti-tumor immune response and late MF/CTCL associated with a loss of immune function mediated by malignant T cells that share regulatory T cell–like properties.

Staphylococcal enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma

“…Some studies have reported IL-17 mRNA and/or protein expression in situ and ex vivo, whereas others reported its absence, despite the presence of IL-22-producing Th17-like cells. 21,[57][58][59]60 The present findings offer a possible explanation for these opposing results; specifically, that the differences in frequency and severity of skin colonization and infection by SE-producing bacteria between different cohorts of patients and even within a single cohort may explain why IL-17 expression differed between these studies and between patients within a single cohort. 21,57,60 The finding that SEA induces IL-17 expression in nonmalignant primary T cells was not unexpected, given that SEA mediates STAT3 activation in these cells, 77 but it was important because it suggests that both malignant and nonmalignant T cells may contribute to IL-17 expression in vivo.…”

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

“…51) and aberrant expression of IL-17. 52 In classical Hodgkin's lymphoma, HSP90 is essential for JAK/STAT signalling, as it activates JAK1 and JAK2. 53 The Ephrin family of tyrosine kinase receptors have also been shown to activate the JAK-STAT3 pathway.…”

Interleukin-13 is overexpressed in cutaneous T-cell lymphoma cells and regulates their proliferation

“…12 In the inflammatory context, cytokines that are derived from inflammatory cells play a key role in restricting immune functions and act concomitantly with suppressive inflammatory cytokines that are secreted by the tumor cells themselves. 13 Attempts to associate a unique cytokine profile with the disease based on skin or blood samples have generally indicated that a shift from Th1 to Th2 cytokine production [14][15][16][17][18] accompanies disease progression. Furthermore, Th2 cell-specific transcription factors, such as GATA-3 and JunB, were highly overexpressed in SS, as detected by cDNA microarray analysis.…”