The role of cytokine signaling in the pathogenesis of cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) displays immunosuppressive properties and phenotypic plasticity. The malignant T-cells in CTCL can possess features of immunomodulating regulatory T cells (Treg) and IL-17-producing helper T cells (Th17) depending on the stimuli they receive from antigen presenting cells and other sources. IL-2-type cytokines activate STAT5 to promote expression of Treg-related FoxP3, while various cytokines can activate STAT3 to induce synthesis of IL-10 and IL-17. When the Treg phenotype is activated in the early stages of CTCL, "immune evasion" can occur, allowing the clonal T cells to expand. Late stages of CTCL lose the FoxP3 expression but continue to express an immunosuppressive cell-surface ligand PD-L1 suggesting that this and possibly other immunosuppressive proteins rather than FoxP3 are critical for the immunosuppressive state in the advanced stages of CTCL. Novel therapeutic agents may potentially exploit the phenotypic plasticity of CTCL such that the malignant T cells become vulnerable to antitumor immunity.