Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein.
Immune escape of tumors in vivo by expression of cellular FLICE-inhibitory protein.
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DOI：
10.1084/jem.190.7.1033
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发表时间：
1999-10-04
影响因子：
15.3
通讯作者：
Offringa, R
中科院分区：
文献类型：
--
作者：
Medema, J P;de Jong, J;van Hall, T;Melief, C J;Offringa, R
抗凋亡蛋白细胞FLICE（Fas相关死亡结构域样IL-1β转化酶）抑制蛋白（cFLIP）在体外保护细胞免受CD 95（APO-1/Fas）诱导的凋亡，并发现在人类黑素瘤中过表达。然而，细胞毒性T细胞诱导的细胞凋亡，这是关键参与体内肿瘤控制，不抑制cFLIP在体外，因为只有CD 95-而不是穿孔素依赖性裂解的影响。这就提出了cFLIP是否足以使T细胞依赖性免疫逃逸的问题。使用两个小鼠肿瘤，我们直接证明cFLIP确实导致体内T细胞免疫逃逸。此外，针对升高的cFLIP表达在体内选择肿瘤细胞。因此，我们的数据表明，CD 95依赖性细胞凋亡构成了一个更突出的机制，肿瘤清除比迄今预期的，这条途径的封锁，可导致肿瘤逃逸，即使当穿孔素途径是操作。
The antiapoptotic protein cellular FLICE (Fas-associated death domain–like IL-1β–converting enzyme) inhibitory protein (cFLIP) protects cells from CD95(APO-1/Fas)-induced apoptosis in vitro and was found to be overexpressed in human melanomas. However, cytotoxic T cell–induced apoptosis, which is critically involved in tumor control in vivo, is not inhibited by cFLIP in vitro, as only CD95- and not perforin-dependent lysis is affected. This calls into question whether cFLIP is sufficient to allow escape from T cell–dependent immunity. Using two murine tumors, we directly demonstrate that cFLIP does result in escape from T cell immunity in vivo. Moreover, tumor cells are selected in vivo for elevated cFLIP expression. Therefore, our data indicate that CD95-dependent apoptosis constitutes a more prominent mechanism for tumor clearance than has so far been anticipated and that blockade of this pathway can result in tumor escape even when the perforin pathway is operational.