Dighe A S, Richards E, Old L J, Schreiber R D
Center for Immunology, Washington University School of Medicine, St. Louis, Missouri 63110.
Immunity. 1994 Sep;1(6):447-56. doi: 10.1016/1074-7613(94)90087-6.
Using a neutralizing monoclonal antibody specific for murine IFN gamma we show that endogenously produced IFN gamma plays an obligate role in mediating LPS-induced rejection of the Meth A fibrosarcoma tumor in syngeneic BALB/c mice. To examine the cellular targets of IFN gamma action, we generated IFN gamma-insensitive tumor cells by stably overexpressing in Meth A a truncated dominant negative form of the murine IFN gamma receptor alpha chain. When implanted in BALB/c mice, IFN gamma-insensitive Meth A cells displayed enhanced tumorigenicity compared with control Meth A cells and were not rejected when tumor-bearing mice were treated with concentrations of LPS that eliminated control tumors. In Meth A immune mice, IFN gamma-insensitive Meth A did not establish tumors while IFN gamma-insensitive tumors grew in a progressive manner. In addition, the IFN gamma-insensitive tumor cells were unable to elicit strong protective immunity to subsequent wild-type tumor challenge. These results show that IFN gamma has direct effects on tumor cell immunogenicity and thus plays an important role in promoting tumor cell recognition and elimination.
使用对鼠IFNγ特异的中和单克隆抗体，我们发现内源性产生的IFNγ在介导LPS诱导的同基因BALB/c小鼠中Meth A纤维肉瘤肿瘤排斥反应中起关键作用。为了研究IFNγ作用的细胞靶点，我们通过在Meth A细胞中稳定过表达截短的显性负性形式的鼠IFNγ受体α链，生成了对IFNγ不敏感的肿瘤细胞。当植入BALB/c小鼠时，与对照Meth A细胞相比，对IFNγ不敏感的Meth A细胞表现出更强的致瘤性，并且当荷瘤小鼠用能消除对照肿瘤的LPS浓度处理时，这些细胞不会被排斥。在Meth A免疫小鼠中，对IFNγ不敏感的Meth A细胞不能形成肿瘤，而对IFNγ不敏感的肿瘤则以渐进方式生长。此外，对IFNγ不敏感的肿瘤细胞不能对随后的野生型肿瘤攻击引发强大的保护性免疫。这些结果表明，IFNγ对肿瘤细胞免疫原性有直接影响，因此在促进肿瘤细胞识别和清除中起重要作用。
