RIG-I 激动剂 SLR14 的瘤内给药可诱导强有力的抗肿瘤反应。

The Tokushima journal of experimental medicine Pub Date : 2019-12-02 Epub Date: 2019-10-10 DOI:10.1084/jem.20190801
Xiaodong Jiang, Viswanathan Muthusamy, Olga Fedorova, Yong Kong, Daniel J Kim, Marcus Bosenberg, Anna Marie Pyle, Akiko Iwasaki
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引用次数: 43

摘要

细胞质核酸感应通路可被触发,以增强对癌症的免疫反应。在这项研究中,我们测试了一种独特的 RIG-I 激动剂--茎环 RNA (SLR) 14 的抗肿瘤活性。在免疫原性肿瘤模型中,我们观察到经 SLR14 处理的小鼠肿瘤生长明显延迟,存活期延长。与单药治疗相比,SLR14 还大大提高了抗 PD1 抗体的抗肿瘤疗效。SLR14主要被肿瘤微环境中的CD11b+髓系细胞吸收,许多与免疫防御相关的基因在治疗后显著上调,同时SLR14治疗的肿瘤中CD8+T淋巴细胞、NK细胞和CD11b+细胞的数量也有所增加。引人注目的是,SLR14 显著抑制了非免疫原性 B16 肿瘤的生长,而且治愈的小鼠产生了免疫记忆。此外,在双侧和肿瘤转移模型中都观察到了全身性抗肿瘤反应。总之,我们的研究结果表明,SLR14 是一种很有前途的治疗性 RIG-I 激动剂,可单独或与现有的免疫疗法结合使用,用于癌症治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Intratumoral delivery of RIG-I agonist SLR14 induces robust antitumor responses.

Cytosolic nucleic acid-sensing pathways can be triggered to enhance immune response to cancer. In this study, we tested the antitumor activity of a unique RIG-I agonist, stem loop RNA (SLR) 14. In the immunogenic tumor models, we observed significant tumor growth delay and an extended survival in SLR14-treated mice. SLR14 also greatly improved antitumor efficacy of anti-PD1 antibody over single-agent treatment. SLR14 was mainly taken up by CD11b+ myeloid cells in the tumor microenvironment, and many genes associated with immune defense were significantly up-regulated after treatment, accompanied by increase in the number of CD8+ T lymphocytes, NK cells, and CD11b+ cells in SLR14-treated tumors. Strikingly, SLR14 dramatically inhibited nonimmunogenic B16 tumor growth, and the cured mice developed an immune memory. Furthermore, a systemic antitumor response was observed in both bilateral and tumor metastasis models. Collectively, our results demonstrate that SLR14 is a promising therapeutic RIG-I agonist for cancer treatment, either alone or in combination with existing immunotherapies.

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