Akagi J, Nakagawa K, Egami H, Ogawa M
Department of Surgery II, Kumamoto University Medical School, Honjo, Japan.
Cancer Immunol Immunother. 1998 Sep;47(1):21-31. doi: 10.1007/s002620050500.
We recently reported that immunization with a recombinant MUC-1 vaccinia virus (rVMUC-1) protected C57BL/6 mice from challenge with DF3/MUC-1-positive syngeneic tumors. To elucidate whether anti-MUC-1 tumor immunity, especially MUC-1-specific cytotoxic T lymphocytes (CTI), can be induced in cancer patients by rVMUC-1, we stimulated the peripheral blood lymphocytes from patients with DF3/MUC-1+ or DF3/MUC-1 colon carcinomas using the autologous monocytes infected with rVMUC-1 (rVAMN). The stimulated T lymphocytes from two patients with DF3/MUC-1-positive colorectal carcinomas (rVPY+T and rVPW+T) demonstrated HLA-unrestricted cytotoxicity against MUC-1, whereas those from the patient with DF3/MUC-1-negative colon carcinoma (rVPA-T) did not. The HLA-unrestricted cytotoxicity was demonstrated by the CD8+ T cells possibly recognizing an epitope present on the tandem repeats. Adoptive immunotherapy who performed three times with patient PY, at 4-week intervals. The adoptive transfer of the first stimulated lymphocytes, demonstrating a high level of HLA-unrestricted cytotoxicity against MUC-1, resulted in the significant reduction of the liver metastasis of patient PY. However, HLA-unrestricted cytotoxicity against MUC-1 was extremely reduced at the second transfer and finally eliminated at the third, whereas the CD4+ T cells demonstrating HLA-class-II-restricted cytotoxicity against MUC-1 predominantly proliferated at the third adoptive immunotherapy treatment. The liver metastasis and the serum levels of tumor markers (carcinoembryonic antigen CA19-9) demonstrated a rapid and marked increment after the second transfer and especially after the third. These results suggest that the HLA-unrestricted cytotoxic CD8+ T cells against MUC-1, induced in patients with DF3/MUC-1+ colorectal carcinomas using rVMUC-1, correlate with the antitumor activity in vivo.
我们最近报道，用重组MUC-1痘苗病毒（rVMUC-1）免疫可保护C57BL/6小鼠免受DF3/MUC-1阳性同基因肿瘤的攻击。为了阐明rVMUC-1是否能在癌症患者中诱导抗MUC-1肿瘤免疫，特别是MUC-1特异性细胞毒性T淋巴细胞（CTI），我们用感染了rVMUC-1的自体单核细胞（rVAMN）刺激DF3/MUC-1+或DF3/MUC-1结肠癌患者的外周血淋巴细胞。两名DF3/MUC-1阳性结直肠癌患者（rVPY+T和rVPW+T）受刺激的T淋巴细胞表现出对MUC-1的HLA非限制性细胞毒性，而DF3/MUC-1阴性结肠癌患者（rVPA-T）的T淋巴细胞则没有。CD8+T细胞可能识别串联重复序列上存在的表位，从而表现出HLA非限制性细胞毒性。对患者PY每隔4周进行3次过继性免疫治疗。首次刺激的淋巴细胞表现出对MUC-1的高水平HLA非限制性细胞毒性，其过继性转移导致患者PY肝转移显著减少。然而，第二次转移时对MUC-1的HLA非限制性细胞毒性极度降低，第三次转移时最终消失，而在第三次过继性免疫治疗时主要增殖的是表现出对MUC-1的HLA-II类限制性细胞毒性的CD4+T细胞。第二次转移后，尤其是第三次转移后，肝转移和肿瘤标志物（癌胚抗原CA19-9）的血清水平迅速显著升高。这些结果表明，用rVMUC-1在DF3/MUC-1+结直肠癌患者中诱导的针对MUC-1的HLA非限制性细胞毒性CD8+T细胞与体内抗肿瘤活性相关。
