Hurwitz A A, Townsend S E, Yu T F, Wallin J A, Allison J P
Howard Hughes Medical Institute, Cancer Research Laboratory, University of California, Berkeley 94720, USA.
Int J Cancer. 1998 Jul 3;77(1):107-13. doi: 10.1002/(sici)1097-0215(19980703)77:1<107::aid-ijc17>3.0.co;2-b.
In recent years, tumor immunotherapy has begun to exploit the emerging knowledge of the mechanisms of T cell activation to enhance the immune responses to tumors. However, many tumors, despite genetic modification to express co-stimulatory molecules or cytokines, are not readily rejected due to their inherently poor immunogenicity. In the present study, we tested whether expression of the co-stimulatory ligand B7-1 and the immunostimulatory cytokines interferon gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) by a mammary carcinoma (SM1) would sufficiently augment its immunogenicity to obtain rejection and immunity. Our findings demonstrate that expression of B7, IFN-gamma, or GM-CSF alone, or co-expression of B7 and GM-CSF did not result in rejection of SM1. However, co-expression of B7 and IFN-gamma was sufficient to result in regression of SM1 tumors by a CD8+ T cell-dependent mechanism. Rejection of the B7/IFN-gamma-expressing SM1 tumor resulted in protection from rechallenge not only with the unmodified SM1 tumor but with another syngeneic mammary tumor. Our data support the idea that although B7 expression alone may not be sufficient for rejection of certain tumors, the immune system may be stimulated to mount an effective anti-tumor immune response by the co-expression of both the co-stimulatory ligand and a cytokine.
近年来，肿瘤免疫疗法已开始利用T细胞激活机制方面的新知识来增强对肿瘤的免疫反应。然而，许多肿瘤尽管经过基因改造以表达共刺激分子或细胞因子，但由于其固有的免疫原性较差，仍不易被排斥。在本研究中，我们测试了乳腺癌（SM1）表达共刺激配体B7-1以及免疫刺激细胞因子干扰素γ（IFN-γ）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）是否会充分增强其免疫原性以实现排斥和免疫。我们的研究结果表明，单独表达B7、IFN-γ或GM-CSF，或B7与GM-CSF的共表达均未导致SM1被排斥。然而，B7与IFN-γ的共表达足以通过CD8+ T细胞依赖性机制导致SM1肿瘤消退。排斥表达B7/IFN-γ的SM1肿瘤不仅能抵抗未修饰的SM1肿瘤的再次攻击，还能抵抗另一种同基因乳腺肿瘤的再次攻击。我们的数据支持这样一种观点，即尽管单独表达B7可能不足以排斥某些肿瘤，但共刺激配体和细胞因子的共表达可能会刺激免疫系统产生有效的抗肿瘤免疫反应。
