αLβ2 Integrin is indispensable for CD8+ T-cell recruitment in experimental pancreatic and hepatocellular cancer
αLβ2 Integrin is indispensable for CD8+ T-cell recruitment in experimental pancreatic and hepatocellular cancer
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DOI：
10.1002/ijc.26223
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发表时间：
2012-05-01
影响因子：
6.4
通讯作者：
Ryschich, Eduard
中科院分区：
文献类型：
--
作者：
Takeichi, Takayuki;Mocevicius, Paulius;Ryschich, Eduard
从外周血中募集活化的白细胞进入肿瘤组织是免疫应答的关键步骤，其由特异性粘附分子如内皮ICAM-1和白细胞β 2-整联蛋白之间的相互作用控制。尽管已经提出肿瘤内皮细胞上粘附分子的减弱表达代表抑制肿瘤内白细胞浸润的机制，但对粘附分子与肿瘤组织中白细胞募集的相关性知之甚少。本研究是第一次调查ICAM-1和β 2-整合素在胰腺癌和肝细胞癌体内白细胞募集中的作用，采用基因敲除小鼠，活体延时显微镜和免疫组织化学进行了研究。我们发现，胰腺癌和肝细胞癌的肿瘤组织中浸润着大量活跃的淋巴样和髓样白细胞，尽管肿瘤血管中的白细胞外渗率很低。LFA-1（也称为aL β 2整联蛋白）的敲除强烈抑制了CD 8 + T细胞的募集，而在ICAM-1-/-和Mac-1-/-小鼠中没有发现白细胞粘附和浸润的显著差异。间质性白细胞迁移的分析表明，肿瘤内白细胞使用haptokinetic类型的迁移，但是，没有显着差异的白细胞迁移之间的任何敲除strains. We的结论是，白细胞招聘在胰腺癌和肝细胞癌是一个缓慢的过程，其动态明显的对比，在急性炎症的高速白细胞招聘。与急性炎症反应相反，只有LFA-1控制胰腺癌和肝细胞癌中CD 8 + T细胞的募集，而ICAM-1和Mac-1则可有可无。
Recruitment of activated leukocytes from peripheral blood into the tumor tissue is a crucial step of the immune response, which is controlled by the interaction between specific adhesion molecules such as endothelial ICAM-1 and leukocyte beta 2-integrins. Although attenuated expression of adhesion molecules on tumor endothelium has been proposed to represent a mechanism, which suppresses the intratumoral leukocyte infiltration, the relevance of adhesion molecules for leukocyte recruitment in tumor tissue is poorly understood. The present study is the first investigation of the role of ICAM-1 and beta 2-integrins in leukocyte recruitment in pancreatic and hepatocellular cancer in vivo, which was studied using knockout mice, intravital time-lapse microscopy and immunohistochemistry. We found that tumor tissue of both pancreatic and hepatocellular cancer was infiltrated with numerous active lymphoid and myeloid leukocytes, although the leukocyte extravasation rate in tumor blood vessels was very low. The knockout of LFA-1 (also known as aL beta 2 integrin) strongly suppressed recruitment of CD8+ T cells whereas no significant differences of leukocyte adhesion and infiltration were found in ICAM-1-/- and Mac-1-/- mice. Analysis of the interstitial leukocyte migration demonstrated that intratumoral leukocytes used haptokinetic type of migration, however, no significant differences of leukocyte migration between any knockout strains were found. We concluded that leukocyte recruitment in pancreatic and hepatocellular cancer is a slow-going process whose dynamics clearly contrasts to a high-speed leukocyte recruitment during acute inflammation. In contrast to acute inflammatory reaction, only LFA-1 controls recruitment of CD8+ T-cells in both pancreatic and hepatocellular cancer, whereas ICAM-1 and Mac-1 are dispensable.