TLR7-Induced Mitochondrial Reactive Oxygen Species Production in Monocyte-derived Dendritic Cells Drives IL-12-Dependent NK Cell Activation and Enhances Antitumor Immunity.
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引用次数: 0
Abstract
Dendritic cell (DC)-based vaccines are promising immunotherapies for cancer. Although DC-based therapies are known to activate tumor-specific T cells, the interplay between DCs and NK cells in this setting is not fully understood. In this study, we demonstrated a novel TLR7/ mitochondrial reactive oxygen species (mROS)/IL-12 axis that drives potent NK cell responses against tumors. We showed that TLR7 activation by imiquimod in peripheral blood monocyte-derived CD11c+ DCs triggered mROS production, leading to enhanced IL-12 secretion and subsequent NK cell activation, as evidenced by increased IFN-γ production and tumor cell cytotoxicity. Notably, mROS neutralization abrogates NK cell-mediated tumor cell lysis, and TLR7-mediated DC activation of NK cells occurs independently of MyD88, suggesting involvement of the noncanonical NF-κB pathway. Our findings provide a rationale for targeting the TLR7/mROS/IL-12 axis to enhance the efficacy of DC-based cancer immunotherapy.
单核细胞衍生树突状细胞中 TLR7 诱导的线粒体活性氧生成驱动 IL-12 依赖性 NK 细胞活化并增强抗肿瘤免疫力
基于树突状细胞(DC)的疫苗是一种很有前景的癌症免疫疗法。虽然已知以 DC 为基础的疗法能激活肿瘤特异性 T 细胞,但这种情况下 DC 与 NK 细胞之间的相互作用尚未完全明了。在这项研究中,我们展示了一种新型的 TLR7/线粒体活性氧(mROS)/IL-12 轴,它能驱动 NK 细胞对肿瘤产生强有力的反应。我们发现,咪喹莫特在外周血单核细胞衍生的 CD11c+ DCs 中激活 TLR7 会触发 mROS 的产生,从而导致 IL-12 分泌增强和随后的 NK 细胞激活,IFN-γ 的产生和肿瘤细胞的细胞毒性增强就是证明。值得注意的是,mROS 中和会减弱 NK 细胞介导的肿瘤细胞溶解,而 TLR7 介导的 DC 对 NK 细胞的活化与 MyD88 无关,这表明非经典 NF-κB 通路的参与。我们的发现为靶向 TLR7/mROS/IL-12 轴以提高基于 DC 的癌症免疫疗法的疗效提供了理论依据。
期刊介绍:
The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)