Increased vessel perfusion predicts the efficacy of immune checkpoint blockade
Increased vessel perfusion predicts the efficacy of immune checkpoint blockade
复制标题
血管灌注增加预测免疫检查点阻断的功效
DOI：
10.1172/jci96582
复制
发表时间：
2018-05-01
影响因子：
15.9
通讯作者：
Huang, Yuhui
中科院分区：
文献类型：
--
作者：
Zheng, Xichen;Fang, Zhaoxu;Huang, Yuhui
免疫检查点阻断（ICB）已在几种类型的癌症中显示出治疗潜力，但仅适用于少数患者。因此，鉴定用于预测ICB反应性的可靠且非侵入性的生物标志物是迫切未满足的需求。在这里，我们表明ICB增加了治疗敏感性EO 771和MMTV-PyVT乳腺肿瘤以及CT 26和MCA 38结肠肿瘤模型中的肿瘤血管灌注，但在治疗抵抗性MCaP 0008和4 T1乳腺肿瘤模型中没有。在敏感的肿瘤模型中，抗细胞毒性T淋巴细胞相关蛋白4或抗程序性细胞死亡1治疗增加血管灌注的能力与其抗肿瘤疗效密切相关。此外，全球增强肿瘤血管灌注可以检测到多普勒超声肿瘤大小的变化之前，预测最终的治疗效果与超过90%的敏感性和特异性。从机制上讲，CD 8（+）T细胞耗竭、IFN-γ中和或IFN-γ受体敲除小鼠中的肿瘤植入消除了ICB的血管灌注增强和抗肿瘤作用。这些结果表明，ICB通过促进CD 8（+）T细胞积聚和IFN-γ产生增加血管灌注，表明血管灌注增加反映了ICB成功激活抗肿瘤T细胞免疫。我们的研究结果表明，血管灌注可以作为一种新的非侵入性指标预测ICB的反应性。
Immune checkpoint blockade (ICB) has demonstrated curative potential in several types of cancer, but only for a small number of patients. Thus, the identification of reliable and noninvasive biomarkers for predicting ICB responsiveness is an urgent unmet need. Here, we show that ICB increased tumor vessel perfusion in treatment-sensitive EO771 and MMTV-PyVT breast tumor as well as CT26 and MCA38 colon tumor models, but not in treatment-resistant MCaP0008 and 4T1 breast tumor models. In the sensitive tumor models, the ability of anti-cytotoxic T lymphocyte-associated protein 4 or anti-programmed cell death 1 therapy to increase vessel perfusion strongly correlated with its antitumor efficacy. Moreover, globally enhanced tumor vessel perfusion could be detected by Doppler ultrasonography before changes in tumor size, which predicted final therapeutic efficacy with more than 90% sensitivity and specificity. Mechanistically, CD8(+) T cell depletion, IFN-gamma neutralization, or implantation of tumors in IFN-gamma receptor knockout mice abrogated the vessel perfusion enhancement and antitumor effects of ICB. These results demonstrated that ICB increased vessel perfusion by promoting CD8(+) T cell accumulation and IFN-gamma production, indicating that increased vessel perfusion reflects the successful activation of antitumor T cell immunity by ICB. Our findings suggest that vessel perfusion can be used as a novel noninvasive indicator for predicting ICB responsiveness.