Wiebke E A, Custer M C, Rosenberg S A, Lotze M T
Surgery Branch, National Cancer Insitute, National Institutes of Health, Bethesda, MD 20892.
J Biol Response Mod. 1990 Apr;9(2):113-26.
Interferon-gamma (IFN) and tumor necrosis factor-alpha (TNF) were examined for their ability to enhance major histocompatibility complex (MHC) expression on a variety of human tumor and normal tissue targets. Enhanced expression of MHC correlated with decreased target susceptibility to lysis by fresh peripheral blood mononuclear cells (PBMCs) and IL-2-augmented PBMCs (aPBL) but not as clearly with cells with lymphokine-activated killer (LAK) activity. These studies revealed maximal MHC enhancement after 48-72 h of incubation in IFN. Resistance to lysis by natural killer (NK) cells was best demonstrated after 72 h. Further, IFN and TNF were synergistic in their effects on MHC expression and induction of resistance of the cultured leukemias K562 and Molt-4 to aPBL effectors. Conversely, LAK susceptibility was usually unaltered after target IFN and TNF treatment. Incubation of fibroblasts and vascular endothelial cells with IFN also consistently resulted in MHC class I enhancement and resistance to NK lysis, whereas LAK susceptibility was variably affected. The brief incubation of fresh PBL in IL-2 (4-6 h) resulted in effectors highly lytic toward cultured cells, but with no activity against fresh tumor. Cultured cell lines treated with IFN and TNF were rendered relatively resistant to lysis by these activated cells. Fresh tumor MHC expression and LAK susceptibility was unchanged after IFN incubation. Additionally, there was no correlation between the level of MHC class I or class II expression and LAK susceptibility to any fresh, uncultured melanoma studied. These data suggest that LAK effectors possess different mechanisms of tumor recognition or lysis than cells with NK activity or cells briefly incubated (4-6 h) in IL-2. The ability of tumor-infiltrating lymphocytes to lyse the cultured autologous tumor target was markedly increased by preincubation of the targets with IFN and TNF. Finally, it appears that IL-2 treatment and the resultant endogenous production of IFN by T-lymphocytes should not adversely affect tumor susceptibility to current immunotherapy using IL-2.
检测了γ干扰素（IFN）和肿瘤坏死因子-α（TNF）增强多种人类肿瘤及正常组织靶细胞上主要组织相容性复合体（MHC）表达的能力。MHC表达增强与新鲜外周血单个核细胞（PBMC）和白细胞介素-2增强的PBMC（aPBL）对靶细胞溶解的敏感性降低相关，但与具有淋巴因子激活的杀伤细胞（LAK）活性的细胞相关性不明显。这些研究显示，在IFN中孵育48 - 72小时后MHC增强达到最大值。自然杀伤（NK）细胞对靶细胞的杀伤抗性在72小时后表现最佳。此外，IFN和TNF在对MHC表达以及诱导培养的白血病细胞K562和Molt - 4对aPBL效应细胞产生抗性方面具有协同作用。相反，靶细胞经IFN和TNF处理后，其对LAK的敏感性通常未改变。用IFN孵育成纤维细胞和血管内皮细胞也始终导致MHC I类分子增强以及对NK杀伤的抗性，而对LAK的敏感性则受到不同程度的影响。新鲜PBL在白细胞介素-2中短暂孵育（4 - 6小时）可产生对培养细胞具有高度杀伤性的效应细胞，但对新鲜肿瘤无活性。经IFN和TNF处理的培养细胞系对这些活化细胞的溶解具有相对抗性。IFN孵育后新鲜肿瘤的MHC表达和对LAK的敏感性未改变。此外，在所研究的任何新鲜、未培养的黑色素瘤中，MHC I类或II类分子的表达水平与对LAK的敏感性之间均无相关性。这些数据表明，LAK效应细胞与具有NK活性的细胞或在白细胞介素-2中短暂孵育（4 - 6小时）的细胞相比，具有不同的肿瘤识别或溶解机制。用IFN和TNF预孵育靶细胞可显著增强肿瘤浸润淋巴细胞对培养的自体肿瘤靶细胞的溶解能力。最后，似乎白细胞介素-2治疗以及由此导致的T淋巴细胞内源性IFN产生不应对当前使用白细胞介素-2的免疫治疗中肿瘤的敏感性产生不利影响。
