STING 激活對(duì)腫瘤脈管系統(tǒng)進(jìn)行重編程并與 VEGFR2 阻斷協(xié)同作用

中文摘要：

IFN 基因刺激因子 （STING） 信號(hào)通路是先天免疫和適應(yīng)性免疫之間的關(guān)鍵聯(lián)系，可誘導(dǎo)抗腫瘤免疫反應(yīng)。STING 在脈管系統(tǒng)中表達(dá)，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(dǎo)的腫瘤血管重塑和基于 STING 的聯(lián)合免疫療法的潛力。內(nèi)皮 STING 表達(dá)與人結(jié)腸癌和乳腺癌中 T 細(xì)胞浸潤(rùn)增強(qiáng)和生存期延長(zhǎng)相關(guān)。使用 STING 激動(dòng)劑 （cGAMP 或 RR-CDA） 的瘤內(nèi) STING 激活使植入癌和自發(fā)性癌癥的腫瘤脈管系統(tǒng)正常化，但在 STING 缺陷小鼠中則不正常。這些是通過(guò) I/II 型 IFN 基因和血管穩(wěn)定基因 （例如 Angpt1 、 Pdgfrb 和 Col4a） 的上調(diào)介導(dǎo)的。非造血細(xì)胞中的 STING 與造血細(xì)胞中的 STING 一樣重要，以誘導(dǎo)外源性 STING 激動(dòng)劑的最大治療效果。STING 激動(dòng)劑的血管正常化作用取決于 I 型 IFN 信號(hào)傳導(dǎo)和 CD8+ T 細(xì)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(diǎn)阻斷 （αPD-1 或 αCTLA-4） 聯(lián)合使用時(shí)數(shù)據(jù)好，導(dǎo)致免疫治療耐藥腫瘤消退。我們的數(shù)據(jù)表明，瘤內(nèi) STING 激活可以使腫瘤脈管系統(tǒng)和腫瘤微環(huán)境正常化，為結(jié)合基于 STING 的免疫療法和抗血管生成療法提供了理論依據(jù)。

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(shí)間期卷：2019;129(10):4350-4364.

在線時(shí)間：2019年7月25日

DOI：doi.org/10.1172/JCI125413.

產(chǎn)品信息：

貨號(hào)：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology（靶點(diǎn)科技）

Clodronate Liposomes氯膦酸鹽脂質(zhì)體助力腫瘤模型巨噬細(xì)胞研究，荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見(jiàn)刊于JCI：

Liposoma巨噬細(xì)胞清除劑ClodronateLiposomes氯膦酸二鈉脂質(zhì)體的材料和方法：