Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA.
Oncoimmunology. 2021 Jun 28;10(1):1939601. doi: 10.1080/2162402X.2021.1939601. eCollection 2021.
Although pharmacological stimulation of TLRs has anti-tumor effects, it has not been determined whether endogenous stimulation of TLRs can lead to tumor rejection. Herein, we demonstrate the existence of an innate anti-glioma NK-mediated circuit initiated by glioma-released miR-1983 within exosomes, and which is under the regulation of galectin-1 (Gal-1). We demonstrate that miR-1983 is an endogenous TLR7 ligand that activates TLR7 in pDCs and cDCs through a 5'-UGUUU-3' motif at its 3' end. TLR7 activation and downstream signaling through MyD88-IRF5/IRF7 stimulates secretion of IFN-β. IFN-β then stimulates NK cells resulting in the eradication of gliomas. We propose that successful immunotherapy for glioma could exploit this endogenous innate immune circuit to activate TLR7 signaling and stimulate powerful anti-glioma NK activity, at least 10-14 days before the activation of anti-tumor adaptive immunity.
虽然 TLRs 的药理学刺激具有抗肿瘤作用，但尚未确定内源性 TLR 刺激是否会导致肿瘤排斥。在此，我们证明了由胶质瘤释放的外泌体中的 miR-1983 启动的先天抗神经胶质瘤 NK 介导的回路的存在，该回路受半乳糖凝集素-1 (Gal-1) 的调节。我们证明 miR-1983 是内源性 TLR7 配体，通过其 3' 末端的 5'-UGUUU-3' 基序在 pDCs 和 cDCs 中激活 TLR7。TLR7 激活和下游信号通过 MyD88-IRF5/IRF7 刺激 IFN-β 的分泌。IFN-β 然后刺激 NK 细胞导致神经胶质瘤的消除。我们提出，成功的神经胶质瘤免疫疗法可以利用这种内源性先天免疫回路来激活 TLR7 信号并刺激强大的抗神经胶质瘤 NK 活性，至少在抗肿瘤适应性免疫激活前 10-14 天。
