Autocrine secretion of fas ligand shields tumor cells from fas-mediated killing by cytotoxic lymphocytes
Autocrine secretion of fas ligand shields tumor cells from fas-mediated killing by cytotoxic lymphocytes
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DOI：
10.1158/0008-5472.can-04-0508
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Levitskaya, J
中科院分区：
文献类型：
--
作者：
Hallermalm, K;De Geer, A;Levitskaya, J
肿瘤对细胞毒性淋巴细胞死亡受体介导的损伤的抵抗机制尚不清楚。葡萄膜黑色素瘤细胞表达Fas，但对旁观者细胞毒性T淋巴细胞或Fas特异性激动性抗体诱导的Fas触发不敏感;这不能归因于肿瘤对T细胞的反击或肿瘤对凋亡的一般抗性。金属蛋白酶抑制剂治疗使葡萄膜黑色素瘤对Fas-mediated细胞毒性敏感。金属蛋白酶抑制剂不影响Fas的表达，但增加Fas配体（FasL）的表面表达，这与可溶性FasL从肿瘤细胞培养上清中的消失有关。从葡萄膜黑色素瘤表面洗脱的FasL特异性抑制用金属蛋白酶抑制剂预处理的肿瘤细胞的细胞毒性T淋巴细胞溶解。除了葡萄膜黑色素瘤，其他肿瘤细胞系的各种细胞来源的金属蛋白酶抑制剂的Fas介导的细胞毒性敏感。我们的研究结果表明，自分泌的FasL屏蔽Fas介导的杀伤细胞毒性淋巴细胞的肿瘤细胞。这定义了肿瘤逃避免疫监视的新机制。
Mechanisms responsible for resistance of tumors to death receptor-mediated damage by cytotoxic lymphocytes are not well understood. Uveal melanoma cells expressed Fas but were insensitive to Fas triggering induced by bystander cytotoxic T lymphocytes or a Fas-specific agonistic antibody; this could not be ascribed to tumor counterattack against T cells or general resistance of the tumors to apoptosis. Treatment with inhibitors of metalloproteases rendered uveal melanomas sensitive to Fas-mediated cytotoxicity. Metalloprotease inhibitors did not affect the expression of Fas but increased the surface expression of Fas ligand (FasL), which correlated with the disappearance of soluble FasL from culture supernatants of tumor cells. FasL eluted from the surface of uveal melanomas specifically inhibited cytotoxic T lymphocyte lysis of tumor cells pretreated with an inhibitor of metalloproteases. In addition to uveal melanomas, a number of other tumor cell lines of various cellular origins were sensitized to Fas-mediated cytotoxicity by metalloprotease inhibitors. Our results show that autocrine secretion of FasL shields tumor cells from Fas-mediated killing by cytotoxic lymphocytes. This defines a novel mechanism of tumor escape from immune surveillance.