Role of spontaneous and interleukin-2-induced natural killer cell activity in the cytotoxicity and rejection of Fas+ and Fas- tumor cells
Role of spontaneous and interleukin-2-induced natural killer cell activity in the cytotoxicity and rejection of Fas+ and Fas- tumor cells
复制标题
DOI：
10.1182/blood.v92.11.4248.423k20_4248_4255
复制
发表时间：
1998-12-01
期刊：
影响因子：
20.3
通讯作者：
Nagarkatti, M
中科院分区：
文献类型：
--
作者：
Bradley, M;Zeytun, A;Nagarkatti, M
在当前的研究中，我们研究了初始的多聚 I:C 或白细胞介素 2 (IL-2) 诱导的自然杀伤 (NK)/淋巴因子激活的杀伤 (LAK) 细胞是否使用穿孔素和/或 pas 配体 (FasL) 来介导细胞毒性。我们将这些发现与小鼠自发地或在IL-2治疗后排斥同源Fas(+)和Fas(-)肿瘤细胞的能力相关联。自发性 NK 细胞介导的细胞毒性主要基于穿孔素，而 Poly I:C 和 IL-2 诱导的 NK/LAK 活性则依赖于 FasL 和穿孔素。在野生型、gld/gld 和穿孔素敲除小鼠中，L1210 Fas(+) 肿瘤靶点比 L1210 Fas(-) 靶点对 Poly I:C 和 IL-2 诱导的细胞毒性更敏感。当L1210 Fas（+）和Fas（-）肿瘤细胞皮下（sc）或腹膜内注射到同基因小鼠中时，Fas（-）肿瘤细胞比Fas（+）肿瘤细胞更早导致死亡。此外，大约 20% 皮下注射 L1210 Fas(-) 肿瘤细胞的小鼠在挑战中存活下来（> 60 天），而所有类似注射 L1210 Fas(-) 肿瘤细胞的小鼠均死亡。当在皮下注射肿瘤细胞的小鼠中尝试使用 IL-2（10,000 U，每周 3 次，持续一周，随后每天一次，持续一周）进行免疫治疗时，IL-2 治疗对携带 L1210 Fas(+)（40% 存活率）肿瘤的小鼠非常有效，但对 L1210 Fas(-)（0% 存活率）肿瘤的小鼠无效。这些数据与以下发现相关：与 L1210 Fas(-) 靶标相比，注射 IL-2 的小鼠的 LAK 细胞对 L1210 Fas(+) 的细胞毒性增加。此外，与携带 L1210 Fas(-) 肿瘤细胞的小鼠相比，携带 L1210 Fas(+) 肿瘤细胞的小鼠表现出肿瘤特异性细胞毒性 T 淋巴细胞 (CTL) 活性增加。我们的研究首次表明，肿瘤靶标上 pas 的表达使它们更具免疫原性，并且更容易受到 CTL 和 IL-2 诱导的 LAK 活性的影响。 Fas(+) 肿瘤细胞对 IL-2 免疫治疗也更敏感。 (C) 1998 年，美国血液学会。
In the current study, we investigated whether the naive, poly I:C or interleukin-2 (IL-2)-induced natural killer (NK)/lymphokine-activated killer (LAK) cells use perforin and/or pas ligand (FasL) to mediated cytotoxicity. We correlated these findings with the ability of mice to reject syngeneic Fas(+) and Fas(-) tumor cells either spontaneously or after IL-2 treatment. The spontaneous NK-cell-mediated cytotoxicity was primarily perforin based, whereas the poly I:C and IL-2-induced NK/LAK activity was both FasL and perforin dependent. L1210 Fas(+) tumor targets were more sensitive than L1210 Fas(-) targets to poly I:C and IL-2-induced cytotoxicity in wild-type, gld/gld, and perforin knockout mice. When L1210 Fas(+) and Fas(-) tumor cells were injected subcutaneously (sc) or intraperitoneally into syngeneic mice, Fas(-) tumor cells caused mortality earlier than Fas(+) tumor cells. Also, approximately 20% of the mice injected sc with L1210 Fas(-) tumor cells survived the challenge(>60 days), whereas all mice injected similarly with L1210 Fas(-) tumor cells died. When immunotherapy using IL-2 (10,000 U, three times/d for a week, followed by once/d for an additional week) was attempted in mice injected sc with tumor cells, IL-2 treatment was very effective against mice bearing L1210 Fas(+) (40% survival) but not L1210 Fas(-) (0% survival) tumors. These data correlated with the finding that the LAK cells from IL-2-injected mice caused increased cytotoxicity against L1210 Fas(+) when compared with L1210 Fas(-) targets. Also, L1210 Fas(+) tumor-bearing mice showed increased tumor-specific cytotoxic T lymphocyte (CTL) activity when compared with those bearing L1210 Fas(-) tumor cells. Together our studies show for the first time that expression of pas on tumor targets makes them more immunogenic as well as susceptible to CTL- and IL-2-induced LAK activity. The Fas(+) tumor cells are also more responsive to immunotherapy with IL-2. (C) 1998 by The American Society of Hematology.