Medical Oncology, CHA Bundang Medical Center, CHA University, Seongnam, South Korea.
Laboratory of Translational Immuno-Oncology, CHA University, Seongnam, South Korea.
J Clin Invest. 2019 Jul 25;129(10):4350-4364. doi: 10.1172/JCI125413.
The stimulator of interferon genes (STING) signaling pathway is a critical link between innate and adaptive immunity, and induces anti-tumor 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 interferon genes and vascular stabilizing genes (e.g., Angpt1, Pdgfrb, and Col4a). STING in non-hematopoietic cells is as important as STING in hematopoietic cells to induce a maximal therapeutic efficacy of exogenous STING agonist. Vascular normalizing effects of STING agonists were dependent on type I interferon 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 anti-angiogenic therapy.
干扰素基因刺激物 (STING) 信号通路是先天免疫和适应性免疫之间的关键环节，可诱导抗肿瘤免疫反应。STING 在脉管系统中表达，但它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以及基于 STING 的联合免疫疗法的潜力。内皮细胞 STING 表达与人类结肠癌和乳腺癌中增强的 T 细胞浸润和延长的生存时间相关。用 STING 激动剂（cGAMP 或 RR-CDA）在植入和自发癌症中激活肿瘤内 STING 可使肿瘤血管正常化，但在 STING 缺陷型小鼠中则不然。这是通过上调 I 型/II 型干扰素基因和血管稳定基因（例如，Angpt1、Pdgfrb 和 Col4a）介导的。非造血细胞中的 STING 与造血细胞中的 STING 一样重要，可诱导外源性 STING 激动剂的最大治疗效果。STING 激动剂的血管正常化作用依赖于 I 型干扰素信号和 CD8+T 细胞。值得注意的是，当与 VEGFR2 阻断和/或免疫检查点阻断（αPD-1 或 αCTLA-4）联合使用时，基于 STING 的免疫疗法效果最佳，导致免疫治疗耐药肿瘤的完全消退。我们的数据表明，肿瘤内 STING 激活可以使肿瘤血管和肿瘤微环境正常化，为联合基于 STING 的免疫疗法和抗血管生成疗法提供了理论依据。
