Toes R E, Offringa R, Blom R J, Brandt R M, van der Eb A J, Melief C J, Kast W M
Department of Immunohematology and Blood Bank, University Hospital Leiden, The Netherlands.
J Immunol. 1995 Apr 1;154(7):3396-405.
Mouse embryo cells (C57BL/6, H-2b) transformed by the E1A and E1B genes of adenovirus type 5 (Ad5E1 MEC) are highly immunogenic. Previously, CTL were cloned from mice immunized with Ad5E1 MEC. These CTL clones were capable of tumor eradication in nude mice, and were directed against the Ad5E1A-encoded decapeptide SGPSNTPPEI, presented by the H-2Db MHC molecule. We have now generated Ad5E1 MEC containing a mutated Ad5E1A-encoded epitope. The mutant Ad5E1 MEC induce a strong CTL response when injected into immunocompetent mice. CTL clones generated against mutant Ad5E1-transformed tumor cells recognize an Ad5E1B-encoded epitope (VNIRNCCYI) in the context of H-2Db. Because this epitope is also present on wild-type Ad5E1 MEC, it is concluded that Ad5E1-transformed tumor cells express at least two CTL epitopes. Interestingly, the lysis of Ad5E1 MEC by the Ad5E1B-specific, but not by the Ad5E1A-specific, CTL clones was strongly diminished by the action of the activated ras oncogene. CTL directed against the Ad5E1B-encoded epitope were, like Ad5E1A-specific CTL, able to eradicate large established Ad5E1-induced tumors in B6 nude mice, demonstrating that CTL activity directed against different CTL epitopes expressed by the same tumor can be exploited for immunotherapy of cancer.
由5型腺病毒（Ad5E1）的E1A和E1B基因转化的小鼠胚胎细胞（C57BL/6，H-2b）具有高度免疫原性。此前，从用Ad5E1 MEC免疫的小鼠中克隆出了细胞毒性T淋巴细胞（CTL）。这些CTL克隆能够在裸鼠中根除肿瘤，并且靶向由H-2Db MHC分子呈递的Ad5E1A编码的十肽SGPSNTPPEI。我们现在已经构建了含有突变的Ad5E1A编码表位的Ad5E1 MEC。当将突变的Ad5E1 MEC注射到免疫活性小鼠中时，会诱导强烈的CTL反应。针对突变的Ad5E1转化肿瘤细胞产生的CTL克隆在H-2Db背景下识别Ad5E1B编码的表位（VNIRNCCYI）。由于该表位也存在于野生型Ad5E1 MEC上，因此得出结论，Ad5E1转化的肿瘤细胞表达至少两种CTL表位。有趣的是，活化的ras癌基因的作用强烈减弱了Ad5E1B特异性而非Ad5E1A特异性CTL克隆对Ad5E1 MEC的裂解作用。与Ad5E1A特异性CTL一样，针对Ad5E1B编码表位的CTL能够根除B6裸鼠中已形成的大型Ad5E1诱导肿瘤，这表明针对同一肿瘤表达的不同CTL表位的CTL活性可用于癌症免疫治疗。
