中文摘要:
IFN 基因刺激因子 (STING) 信号通路是先天免疫和适应性免疫之间的关键联系,可诱导抗肿瘤免疫反应。STING 在脉管系统中表达,但其在肿瘤血管生成中的作用尚未阐明。在这里,我们研究了 STING 诱导的肿瘤血管重塑和基于 STING 的联合免疫疗法的潜力。内皮 STING 表达与人结肠癌和乳腺癌中 T 细胞浸润增强和生存期延长相关。使用 STING 激动剂 (cGAMP 或 RR-CDA) 的瘤内 STING 激活使植入癌和自发性癌症的肿瘤脉管系统正常化,但在 STING 缺陷小鼠中则不正常。这些是通过 I/II 型 IFN 基因和血管稳定基因 (例如 Angpt1 、 Pdgfrb 和 Col4a) 的上调介导的。非造血细胞中的 STING 与造血细胞中的 STING 一样重要,以诱导外源性 STING 激动剂的最大治疗效果。STING 激动剂的血管正常化作用取决于 I 型 IFN 信号传导和 CD8+ T 细胞。值得注意的是,基于 STING 的免疫疗法与 VEGFR2 阻断和/或免疫检查点阻断 (αPD-1 或 αCTLA-4) 联合使用时数据好,导致免疫治疗耐药肿瘤消退。我们的数据表明,瘤内 STING 激活可以使肿瘤脉管系统和肿瘤微环境正常化,为结合基于 STING 的免疫疗法和抗血管生成疗法提供了理论依据。
英文摘要:
The stimulator of IFN genes (STING) signaling pathway is a critical link between innate and adaptive immunity and induces antitumor immune responses. STING is expressed in vasculatures, but its role in tumor angiogenesis has not been elucidated. Here, we investigated STING-induced tumor vascular remodeling and the potential of STING-based combination immunotherapy. Endothelial STING expression was correlated with enhanced T cell infiltration and prolonged survival in human colon and breast cancer. Intratumoral STING activation with STING agonists (cGAMP or RR-CDA) normalized tumor vasculatures in implanted and spontaneous cancers, but not in STING-deficient mice. These were mediated by upregulation of type I/II IFN genes and vascular stabilizing genes (e.g., Angpt1, Pdgfrb, and Col4a). STING in nonhematopoietic cells is as important as STING in hematopoietic cells for inducing a maximal therapeutic efficacy of exogenous STING agonists. Vascular normalizing effects of STING agonists were dependent on type I IFN signaling and CD8+ T cells. Notably, STING-based immunotherapy was maximally effective when combined with VEGFR2 blockade and/or immune-checkpoint blockade (αPD-1 or αCTLA-4), leading to complete regression of immunotherapy-resistant tumors. Our data show that intratumoral STING activation can normalize tumor vasculature and the tumor microenvironment, providing a rationale for combining STING-based immunotherapy and antiangiogenic therapy.
论文信息:
论文题目: STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade
期刊名称:J Clin Invest.
时间期卷:2019;129(10):4350-4364.
在线时间:2019年7月25日
DOI:doi.org/10.1172/JCI125413.
产品信息:
货号:CP-005-005
规格:5ml+5ml
品牌:Liposoma
产地:荷兰
名称:Clodronate Liposomes and Control Liposomes
办事处:Target Technology(靶点科技)
Clodronate Liposomes氯膦酸盐脂质体助力肿瘤模型巨噬细胞研究,荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于JCI:
Liposoma巨噬细胞清除剂ClodronateLiposomes氯膦酸二钠脂质体的材料和方法: