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LAK細胞の発現する膜結合型リンフォトキシンの癌細胞障害活性の解析

LAK细胞表达的膜结合淋巴毒素的癌细胞毒活性分析

基本信息

批准号：
05807106
负责人：
ABE Yasuhito
金额：
$ 1.22万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05807106/
关键词：
LAK cell membrane lymphotoxin tumor cell killing ICAM-1 癌細胞障害活性

项目摘要

This research was aimed to improve clinical effects of adoptive immunotherapy of cancer. For this purpose, mechanisms underlying the target tumor cell killing of LAK cells were investigated from the point of membrance-associated lymphotoxin (mLT) expressred on LAK cells, which we originally reported. In an attempt trying to investigate using cloned cells, cloning of LAK cells were carried out. Several lines of LAK cell clones were established, however, the expression of mLT on all these clones were too low to use them in the analysis of mLT.Therefore, conventional LAK cells were employed in this research. Using conventional LAK cells, several novel evidences came out. Novel tumor cell killing activity of LAK cells other than conventional NK and LAK killing activity were indentified, which was closely related with mLT but not soluble secreted LT.The novel killing activity was evident in a short term killing assay system using ^<51>Cr but not necessarily evident on long term killing assay which was related with cytokine secreted by LAK cells. The effect of mLT was executed via unidentified receptor but via two TNF receptors, to which soluble LT binds and sends signals. LAK cells expressing mLT up-regulated ICAM-1 expression on target tumor cells, which plays important role in target tumor cell killing by LAK cells. This up-regulating effect on ICAM-1 expression by LAK cells was not exerted by mLT itself, but by an unidenntified membrane factor on LAK cells. This effect was not exerted by soluble factors secreted by LAK cells. The identification of the mLT-related ICAM-1 up-regulating membrane factor of LAK cells would bring out an improvement in adoptive immunotherapy.

本研究旨在提高肿瘤过继免疫治疗的临床效果。为此，我们从LAK细胞膜相关光敏素（mLT）表达的角度探讨了LAK细胞杀伤靶肿瘤细胞的机制。为了尝试使用克隆细胞进行研究，进行了LAK细胞的克隆。建立了多株LAK细胞克隆，但其mLT的表达均较低，不能用于mLT的分析，因此本研究采用常规LAK细胞。利用常规LAK细胞，获得了一些新的证据。发现LAK细胞具有不同于传统NK细胞和LAK细胞的新的肿瘤细胞杀伤活性，这种新的杀伤活性与mLT密切相关，而与可溶性分泌型LT无关。这种新的杀伤活性在以~（133）Cr为靶点的短期杀伤试验中明显<51>，但在与LAK细胞分泌的细胞因子相关的长期杀伤试验中不一定明显。mLT的作用是通过未鉴定的受体，但通过两个TNF受体，可溶性LT结合并发送信号。表达mLT的LAK细胞可上调靶肿瘤细胞表面ICAM-1的表达，这在LAK细胞杀伤靶肿瘤细胞中起重要作用。mLT对LAK细胞ICAM-1表达的上调作用不是由mLT本身发挥的，而是由LAK细胞上的一种未被修饰的膜因子发挥的。LAK细胞分泌的可溶性因子不具有这种作用。mLT相关ICAM-1上调LAK细胞膜因子的鉴定将为过继免疫治疗带来新的进展。