Synergistic enhancement of cellular immune responses by the novel Toll receptor 7/8 agonist 3M-007 and interferon-γ: implications for therapy of cutaneous T-cell lymphoma

Abstract

Cutaneous T-cell lymphoma (CTCL) is responsive at all stages to immunotherapy. We determined whether a novel agonist for Toll-like receptor (TLR) 7/8 (3M-007) combined with either interferon-γ (IFN-γ) or interleukin-15 (IL-15) would enhance patients’ immune responses in vitro. Our data demonstrate that IFN-γ or IL-15 in combination with 007 significantly increases patients’ natural killer (NK) cytolytic activity against CTCL tumor cell lines and synergistically induces dendritic cell cytokines, compared to 007 alone. Microarray studies of gene expression of patients’ peripheral blood mononuclear cells (PBMCs) primed with IFN-γ followed by stimulation with 007 identified significant up-regulation of the expression of IL-12 p35 (α-chain), IL-12 p40 (β-chain), and nine IFN-α genes. Importantly, the underlying mechanism of increased levels of IFN-α and IL-12 from combined treatment appears to involve IFN regulatory factor 8 (IRF-8). These results further support our hypothesis that combinations of biological modifiers activating different arms of the immune system may provide significant therapeutic benefits for patients with advanced CTCL.

Keywords:

• CTCL
• immunotherapy
• TLR7/8 agonist
• IFN-γ
• IRF-8

Acknowledgements

This work was supported in part by grants from the National Cancer Institute, R01 CA122569, R01 CA132098, and a Translational Research grant from the Leukemia and Lymphoma Society. A.V.K. is supported by NCI T32 CA09171. M.K.S. was supported by a grant from the Doris Duke Charitable Foundation. The project used the Wistar Genomics facility, supported by P30 CA010815.

We are grateful to Dr. Giorgio Trinchieri for his suggestions.

Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.