Department of Dermatology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Leuk Lymphoma. 2011 Oct;52(10):1970-9. doi: 10.3109/10428194.2011.582202.
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.
皮肤 T 细胞淋巴瘤（CTCL）在各个阶段均对免疫疗法有反应。我们确定了一种新型 Toll 样受体（TLR）7/8 的激动剂（3M-007）与干扰素-γ（IFN-γ）或白细胞介素-15（IL-15）联合使用是否会增强患者的体外免疫反应。我们的数据表明，IFN-γ或 IL-15 与 007 联合使用可显著提高 NK 细胞对 CTCL 肿瘤细胞系的细胞毒性，与单独使用 007 相比，007 联合使用还可协同诱导树突状细胞细胞因子。对经 IFN-γ 预处理的患者外周血单核细胞（PBMC）进行基因表达微阵列研究，然后用 007 刺激，鉴定出 IL-12 p35（α 链）、IL-12 p40（β 链）和九个 IFN-α 基因的表达显著上调。重要的是，联合治疗中 IFN-α 和 IL-12 水平升高的潜在机制似乎涉及干扰素调节因子 8（IRF-8）。这些结果进一步支持了我们的假设，即激活免疫系统不同分支的生物调节剂联合使用可能为晚期 CTCL 患者提供显著的治疗益处。
