STING 激活對腫瘤脈管系統進行重編程并與 VEGFR2 阻斷協同作用

更新時間：2025-01-14 點擊次數：1417次

中文摘要：

IFN 基因刺激因子（STING）信號通路是先天免疫和適應性免疫之間的關鍵聯系，可誘導抗腫瘤免疫反應。STING 在脈管系統中表達，但其在腫瘤血管生成中的作用尚未闡明。在這里，我們研究了 STING 誘導的腫瘤血管重塑和基于 STING 的聯合免疫療法的潛力。內皮 STING 表達與人結腸癌和乳腺癌中 T 細胞浸潤增強和生存期延長相關。使用 STING 激動劑（cGAMP 或 RR-CDA）的瘤內 STING 激活使植入癌和自發性癌癥的腫瘤脈管系統正常化，但在 STING 缺陷小鼠中則不正常。這些是通過 I/II 型 IFN 基因和血管穩定基因（例如 Angpt1 、 Pdgfrb 和 Col4a）的上調介導的。非造血細胞中的 STING 與造血細胞中的 STING 一樣重要，以誘導外源性 STING 激動劑的最大治療效果。STING 激動劑的血管正常化作用取決于 I 型 IFN 信號傳導和 CD8+ T 細胞。值得注意的是，基于 STING 的免疫療法與 VEGFR2 阻斷和/或免疫檢查點阻斷（αPD-1 或 αCTLA-4）聯合使用時數據好，導致免疫治療耐藥腫瘤消退。我們的數據表明，瘤內 STING 激活可以使腫瘤脈管系統和腫瘤微環境正常化，為結合基于 STING 的免疫療法和抗血管生成療法提供了理論依據。

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.

論文信息：

論文題目： STING activation reprograms tumor vasculatures and synergizes with VEGFR2 blockade

期刊名稱：J Clin Invest.

時間期卷：2019;129(10):4350-4364.

在線時間：2019年7月25日

DOI：doi.org/10.1172/JCI125413.

產品信息：

貨號：CP-005-005

規格：5ml+5ml

品牌：Liposoma

產地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes