Synthetic Imidazoquinolines Potently and Broadly Activate the Cellular Immune Response of Patients with Cutaneous T-Cell Lymphoma: Synergy with Interferon-γ Enhances Production of Interleukin-12

Advanced cutaneous T-cell lymphoma (CTCL) is typically associated with a variety of profound defects of cellular immunity, including depressed dendritic cell numbers and function. Therefore, we investigated the ability of synthetic imidazoquinolines, which are agonists for Toll-like receptors (TLRs) 7 and 8, to enhance in vitro the cell-mediated immunity of patients with leukemic CTCL and Sézary syndrome. Patients' peripheral blood mononuclear cells (PBMCs) stimulated with the TLR7 agonist 3M-001 produced high levels of interferon (IFN)–α, and the TLR8 agonist 3M-002 potently induced predominantly interleukin (IL)–12 and IFN-γ Marked upregulation of CD69 and CD25 on natural killer (NK) cells and T cells from patients and an increase in NK cytolytic activity was also observed. We further demonstrate that priming of patients' PBMCs with IFN-γ has the ability to synergistically enhance the production of IL-12 induced by a synthetic agonist for TLR8. The underlying mechanisms of increased IL-12 production in response to priming with IFN appears to involve an increase in IL-12 p35 and IL-12 p40 gene transcription and a decrease in IL-10 levels upon stimulation with the TLR8 agonist. Our data demonstrate the ability of imidazoquinolines to potently stimulate cellular immune responses of patients with CTCL and emphasizes the benefit of using a combination of biologic modifiers to further enhance their immune responses.