Tada Yuji, O-Wang Jiyang, Takiguchi Yuichi, Tatsumi Koichiro, Kuriyama Takayuki, Tagawa Masatoshi
Division of Pathology, Chiba Cancer Center Research Institute, Chuo-ku, Chiba 260-8717, Japan.
Int J Mol Med. 2002 Mar;9(3):281-5.
Interaction between Fas and Fas ligand (FasL) induces apoptotic cell death of Fas-positive cells. Expression of FasL on tumors therefore possibly kills activated Fas-positive cytotoxic T cells that infiltrated into the tumors and consequently the tumors can evade from systemic immune responses. Previous studies however showed that forced expression of FasL in tumors induced neutrophil-mediated inflammatory reactions and accordingly produced T cell independent antitumor effects in the inoculated animals. We then analyzed the FasL-mediated antitumor responses with genetically mutated mice. Murine lung carcinoma (A11) cells transfected with the FasL gene (A11/FasL), which was able to kill Fas-positive B cells, did not form subcutaneous tumors and produced few lung spontaneous metastatic foci in immunocompetent mice. The mice that rejected A11/FasL cells developed tumor-specific protective immunity. A11/FasL cells were also rejected in T cell-defective nude mice and in CD18-deficient mice which showed impaired neutrophil functions, but not in Fas-defective (lpr/lpr) mutant mice. Antitumor activities on A11 cells were dependent on the number of co-injected A11/FasL cells but those on irrelevant B16 murine melanoma cells were not produced even with a large number of co-injected A11/FasL cells. In contrast to previous reports, the present study implies that T cells can also be effectors of FasL-mediated antitumor responses and neutrophils are not absolutely required for the responses.
Fas与Fas配体（FasL）之间的相互作用可诱导Fas阳性细胞发生凋亡性细胞死亡。因此，肿瘤上FasL的表达可能会杀死浸润到肿瘤中的活化Fas阳性细胞毒性T细胞，从而使肿瘤能够逃避全身免疫反应。然而，先前的研究表明，在肿瘤中强制表达FasL会诱导中性粒细胞介导的炎症反应，从而在接种动物中产生不依赖T细胞的抗肿瘤作用。然后，我们用基因敲除小鼠分析了FasL介导的抗肿瘤反应。用能够杀死Fas阳性B细胞的FasL基因转染的小鼠肺癌（A11）细胞（A11/FasL），在免疫功能正常的小鼠中不会形成皮下肿瘤，并且很少产生肺自发转移灶。排斥A11/FasL细胞的小鼠产生了肿瘤特异性保护性免疫。A11/FasL细胞在T细胞缺陷的裸鼠和中性粒细胞功能受损的CD18缺陷小鼠中也被排斥，但在Fas缺陷（lpr/lpr）突变小鼠中则不会。对A11细胞的抗肿瘤活性取决于共注射的A11/FasL细胞的数量，但即使共注射大量的A11/FasL细胞，对无关的B16小鼠黑色素瘤细胞也不会产生抗肿瘤活性。与先前的报道相反，本研究表明T细胞也可以是FasL介导的抗肿瘤反应的效应细胞，并且中性粒细胞并非该反应绝对必需的。
