Fas ligand on tumor cells mediates inactivation of neutrophils
Fas ligand on tumor cells mediates inactivation of neutrophils
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DOI：
10.4049/jimmunol.171.3.1183
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发表时间：
2003-08-01
影响因子：
4.4
通讯作者：
Yang, BC
中科院分区：
文献类型：
--
作者：
Chen, YL;Chen, SH;Yang, BC
Fas配体（FasL）在肿瘤细胞（肿瘤FasL）上的表达与其逃避免疫监视有关。在这项研究中，我们研究了FasL相关的免疫逃逸的细胞机制，使用黑色素瘤B16 F10衍生细胞作为模型。与携带增强型绿色荧光蛋白-N1质粒（FasL（高）肿瘤细胞）的转染子相比，携带FasL特异性核酶的转染子表达低水平的FasL（FasL（低）肿瘤细胞）。当皮下注射时在C57 BL/6小鼠中，FasL（低）肿瘤细胞比FasL（高）黑素瘤细胞生长得更慢。FasL（高）肿瘤细胞表现出更强烈的嗜酸性浸润伴随着多个坏死区比FasL（低）肿瘤细胞。在中性粒细胞耗竭的小鼠中，FasL（低）肿瘤的平均大小显著增加，但FasL（高）肿瘤的平均大小没有显著增加。一致地，局部注射LPS以募集/激活中性粒细胞显著延迟了C57 BL/6和非肥胖糖尿病/SCID小鼠中FasL（低）肿瘤细胞的肿瘤形成，并且略微延迟了FasL高肿瘤细胞的肿瘤形成。中性粒细胞在体外杀死FasL（低）黑色素瘤细胞比FasL高黑色素瘤细胞更有效。FasL高水平黑色素瘤细胞对中性粒细胞杀伤的抵抗与中性粒细胞活化受损相关，如明胶酶B分泌减少、活性氧产生减少、CD 11 B表面表达和FasL转录减少所示。局部转移富含酪蛋白或PMA处理的中性粒细胞延迟黑色素瘤细胞的肿瘤形成。总之，肿瘤FasL使中性粒细胞失活是肿瘤细胞逃避免疫攻击的重要机制。
The expression of Fas ligand (FasL) on tumor cells (tumor FasL) has been implicated in their evasion of immune surveillance. In this study, we investigated the cellular mechanism for FasL-associated immune escape using melanoma B16F10-derived cells as a model. Transfectants carrying FasL-specific ribozymes expressed low levels of FasL (FasL(low) tumor cells) as compared with those carrying enhanced green fluorescent protein-N1 plasmids (FasL(high) tumor cells). When injected s.c. into C57BL/6 mice, FasL(low) tumor cells grew more slowly than did FasL(high) melanoma cells. FasL(high) tumor cells showed more intensive neutrophilic infiltration accompanied by multiple necrotizing areas than did FasL(low) tumor cells. The average size of FasL(low) tumors, but not of FasL(high) tumors, was significantly enhanced in mice depleted of neutrophils. Consistently, a local injection of LPS to recruit/activate neutrophils significantly delayed tumor formation by FasL(low) tumor cells, and slightly retarded that of FasL high tumor cells in both C57BL/6 and nonobese diabetic/SCID mice. Neutrophils killed FasL(low) melanoma cells more effectively than FasL high melanoma cells in vitro. The resistance of FasL high melanoma cells to being killed by neutrophils was correlated with impaired neutrophil activation, as demonstrated by reductions in gelatinase B secretion, reactive oxygen species production, and the surface expression of CD11b and the transcription of FasL. Local transfer of casein-enriched or PMA-treated neutrophils delayed tumor formation by melanoma cells. Taken together, inactivation of neutrophils by tumor FasL is an important mechanism by which tumor cells escape immune attack.