Mukherjee P, Ginardi A R, Tinder T L, Sterner C J, Gendler S J
Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Arizona 85259, USA.
Clin Cancer Res. 2001 Mar;7(3 Suppl):848s-855s.
We have reported previously that MUC1 transgenic mice with spontaneous tumors of the pancreas (designated MET) naturally develop MHC class I-restricted, MUC1-specific CTLs as tumors progress (P. Mukherjee et al., J. Immunol., 165: 3451-3460, 2000). From these MET mice, we have isolated, expanded, and cloned naturally occurring MUC1-specific CTLs in vitro. In this report, we show that the CTL line is predominantly CD8+ T cells and expresses T-cell receptor Vbeta chains 5.1/5.2, 11, 13, and 2 and Valpha chains 2, 8.3, 3.2, and 11.1/11.2. These CTLs recognize several epitopes on the MUC1 tandem repeat with highest affinity to APGSTAPPA. The CTL clone, on the other hand, is 100% CD8+ cells and expresses a single Vbeta chain of 5.1/5.2 and Valpha2. It recognizes only the H-2Db class I-restricted epitope of MUC1, APGSTAPPA. When adoptively transferred, the CTLs were effective in eradicating MUC1-expressing injected tumor cells including mammary gland cells (C57mg) and B16 melanomas. These results suggest that MUC1-specific CTLs are capable of possibly preventing, or at least substantially delaying, MUC1-expressing tumor formation. To our knowledge, this is the first evidence that demonstrates that the naturally occurring MUC1-specific CTLs isolated from one tumor model has antitumor effects on other MUC1-expressing tumors in vivo. Therefore, our data confirm that MUC1 is an important tumor rejection antigen and can serve as a target for immunotherapy.
我们之前报道过，患有自发性胰腺肿瘤的MUC1转基因小鼠（命名为MET）随着肿瘤进展会自然产生MHC I类限制性、MUC1特异性CTL（P. 穆克吉等人，《免疫学杂志》，165: 3451 - 3460，2000年）。从这些MET小鼠中，我们在体外分离、扩增并克隆了天然存在的MUC1特异性CTL。在本报告中，我们表明CTL系主要是CD8 + T细胞，并表达T细胞受体Vβ链5.1/5.2、11、13和2以及Vα链2、8.3、3.2和11.1/11.2。这些CTL识别MUC1串联重复序列上的多个表位，对APGSTAPPA亲和力最高。另一方面，CTL克隆是100%的CD8 + 细胞，表达单一的Vβ链5.1/5.2和Vα2。它仅识别MUC1的H - 2Db I类限制性表位APGSTAPPA。当进行过继转移时，CTL能有效根除表达MUC1的注射肿瘤细胞，包括乳腺细胞（C57mg）和B16黑色素瘤。这些结果表明，MUC1特异性CTL有可能预防或至少显著延迟表达MUC1的肿瘤形成。据我们所知，这是首个证据，证明从一个肿瘤模型中分离出的天然存在的MUC1特异性CTL在体内对其他表达MUC1的肿瘤具有抗肿瘤作用。因此，我们的数据证实MUC1是一种重要的肿瘤排斥抗原，可作为免疫治疗的靶点。
