IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells
IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells
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DOI：
10.1172/jci44952
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Evans, Sharon S.
中科院分区：
文献类型：
--
作者：
Fisher, Daniel T.;Chen, Qing;Evans, Sharon S.
免疫细胞是肿瘤进展的关键调节因子，其通常通过其释放细胞因子介导。炎性细胞因子如IL-6通过驱动肿瘤细胞的生长和存活发挥促肿瘤活性。然而，这些细胞因子是否也有一个作用，在募集介质的适应性抗癌免疫尚未调查。在这里，我们报告了肿瘤反应性CD 8（+）T细胞通过微血管检查点的稳态运输在肿瘤中是有限的，尽管存在炎性细胞因子。荷瘤小鼠的活体成像显示，全身热疗法（核心温度升高至39.5摄氏度+/- 0.5摄氏度，持续6小时）激活了肿瘤血管中的IL-6反式信号程序，该程序修饰了血管系统，从而可以支持CD 8（+）效应/记忆T细胞（Tems）进入肿瘤的增强运输。在全身热治疗期间，伴随的TREM肿瘤浸润减少导致Tem/Treg比率显著增强。从机制上讲，由非造血基质细胞产生的IL-6与可溶性IL-6受体-a和热诱导的gp 130协同作用，促进肿瘤中细胞毒性T细胞的E/P-选择素和ICAM-1依赖性外渗。在小鼠肿瘤和患者肿瘤外植体中，IL-6/可溶性IL-6受体-a融合蛋白诱导血管粘附的平行增加。最后，在IL-6依赖的肿瘤血管的Tem运输许可和肿瘤靶点的凋亡之间建立了因果关系。这些发现表明，独特的富含IL-6的肿瘤微环境可用于创建治疗窗口，以增强T细胞介导的抗肿瘤免疫和免疫治疗。
Immune cells are key regulators of neoplastic progression, which is often mediated through their release of cytokines. Inflammatory cytokines such as IL-6 exert tumor-promoting activities by driving growth and survival of neoplastic cells. However, whether these cytokines also have a role in recruiting mediators of adaptive anticancer immunity has not been investigated. Here, we report that homeostatic trafficking of tumor-reactive CD8(+) T cells across microvascular checkpoints is limited in tumors despite the presence of inflammatory cytokines. Intravital imaging in tumor-bearing mice revealed that systemic thermal therapy (core temperature elevated to 39.5 degrees C +/- 0.5 degrees C for 6 hours) activated an IL-6 trans-signaling program in the tumor blood vessels that modified the vasculature such that it could support enhanced trafficking of CD8(+) effector/memory T cells (Tems) into tumors. A concomitant decrease in tumor infiltration by Tregs during systemic thermal therapy resulted in substantial enhancement of Tem/Treg ratios. Mechanistically, IL-6 produced by nonhematopoietic stromal cells acted cooperatively with soluble IL-6 receptor-a and thermally induced gp130 to promote E/P-selectin- and ICAM-1-dependent extravasation of cytotoxic T cells in tumors. Parallel increases in vascular adhesion were induced by IL-6/soluble IL-6 receptor-a fusion protein in mouse tumors and patient tumor explants. Finally, a causal link was established between IL-6-dependent licensing of tumor vessels for Tem trafficking and apoptosis of tumor targets. These findings suggest that the unique IL-6-rich tumor microenviromnent can be exploited to create a therapeutic window to boost T cell-mediated antitumor immunity and immunotherapy.