Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
The First Affiliated Hospital, Nanchang University, Nanchang, China.
J Leukoc Biol. 2021 Dec;110(6):1197-1208. doi: 10.1002/JLB.5MA0421-013R. Epub 2021 May 14.
Macrophage phagocytosis plays essential roles in antitumor immunity. CD47/SIRPα phagocytosis checkpoint blockade has demonstrated therapeutic potential in several hematopoietic cancers, but recent clinical studies reported very limited efficacy against solid malignancies. Here, we show that polyinosinic-polycytidylic acid (Poly(I:C)), a synthetic analog of double-stranded RNA, enhances the antitumor activity of CD47 blockade in colorectal cancer in vitro and in vivo. Poly(I:C) activation leads to a potent immune response characterized by the production of proinflammatory cytokines, especially IL-6. Stimulation with IL-6 promotes the PI3K signaling and cytoskeletal reorganization required for macrophage phagocytosis mediated by CD47 blockade. Our findings demonstrate the potential of Poly(I:C) to synergize the efficacy of CD47 blockade therapy and a novel role for IL-6 in macrophage phagocytosis, which provide new strategy for combinational cancer immunotherapy.
巨噬细胞吞噬作用在抗肿瘤免疫中发挥着重要作用。CD47/SIRPα吞噬检查点阻断在几种血液系统癌症中显示出治疗潜力，但最近的临床研究报告称，其对实体恶性肿瘤的疗效非常有限。在这里，我们表明，聚肌苷酸-聚胞苷酸（Poly（I：C）），一种双链 RNA 的合成类似物，增强了 CD47 阻断在结直肠癌中的抗肿瘤活性，无论是在体外还是体内。Poly（I：C）的激活导致强烈的免疫反应，其特征是产生促炎细胞因子，特别是 IL-6。用 IL-6 刺激可促进 PI3K 信号转导和细胞骨架重排，这是由 CD47 阻断介导的巨噬细胞吞噬作用所必需的。我们的研究结果表明，Poly（I：C）具有增强 CD47 阻断治疗效果的潜力，以及 IL-6 在巨噬细胞吞噬作用中的新作用，这为联合癌症免疫治疗提供了新策略。
