Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells.
Homing to solid cancers: a vascular checkpoint in adoptive cell therapy using CAR T-cells.
复制标题
将固体癌的归巢：使用CAR T细胞疗法的血管检查点。
DOI：
10.1042/bst20150254
复制
发表时间：
2016-04-15
影响因子：
3.9
通讯作者：
Mohammed RN
中科院分区：
文献类型：
--
作者：
Ager A;Watson HA;Wehenkel SC;Mohammed RN
过继性 T 细胞疗法治疗癌症患者的成功取决于转移的 T 淋巴细胞发现并浸润癌组织。对于静脉内转移的 T 细胞，这意味着从肿瘤血管中排出血流（外渗）。在发炎组织中，外渗的一个关键事件是 T 细胞在血管内的捕获、滚动和停滞，然后穿过血管壁进入组织。这取决于 T 细胞上选择素、整合素和趋化因子受体各自配体的协调信号传导，这些配体在发炎血管上上调。小鼠的临床数据和实验研究表明，肿瘤血管对炎症刺激无反应，并且细胞毒性 CD8+ T 淋巴细胞的募集效率不高。有趣的是，有些违反直觉的是，抗血管生成治疗可以促进肿瘤的 CD8+ T 细胞浸润，并提高过继性 CD8+ T 细胞治疗的疗效。抗血管生成治疗不是抑制肿瘤血管生成，而是通过促进周细胞募集、增加肿瘤血管灌注并使肿瘤血管对炎症刺激敏感来“正常化”（成熟）肿瘤血管。目前正在探索多种不同的方法，通过操纵 T 细胞和肿瘤血管上归巢相关分子的表达来增加招募。未来的研究应该解决这些方法是否可以提高过继性 T 细胞疗法对实体血管癌患者的疗效。
The success of adoptive T-cell therapies for the treatment of cancer patients depends on transferred T-lymphocytes finding and infiltrating cancerous tissues. For intravenously transferred T-cells, this means leaving the bloodstream (extravasation) from tumour blood vessels. In inflamed tissues, a key event in extravasation is the capture, rolling and arrest of T-cells inside blood vessels which precedes transmigration across the vessel wall and entry into tissues. This depends on co-ordinated signalling of selectins, integrins and chemokine receptors on T-cells by their respective ligands which are up-regulated on inflamed blood vessels. Clinical data and experimental studies in mice suggest that tumour blood vessels are anergic to inflammatory stimuli and the recruitment of cytotoxic CD8+ T-lymphocytes is not very efficient. Interestingly, and somewhat counter-intuitively, anti-angiogenic therapy can promote CD8+ T-cell infiltration of tumours and increase the efficacy of adoptive CD8+ T-cell therapy. Rather than inhibit tumour angiogenesis, anti-angiogenic therapy ‘normalizes’ (matures) tumour blood vessels by promoting pericyte recruitment, increasing tumour blood vessel perfusion and sensitizing tumour blood vessels to inflammatory stimuli. A number of different approaches are currently being explored to increase recruitment by manipulating the expression of homing-associated molecules on T-cells and tumour blood vessels. Future studies should address whether these approaches improve the efficacy of adoptive T-cell therapies for solid, vascularized cancers in patients.