ACTIVE SPECIFIC IMMUNE-INDUCTION BY TUMOR-ANTIGEN DERIVED-PEPTIDE RECOGNIZED BY T CELLS

我们检测了10例乳腺癌、31例食道癌和4例胰腺癌组织中MAGE-1、MAGE-3和人类白细胞抗原A1基因的表达。没有携带人类白细胞抗原A1的患者。乳腺癌组织中MAGE-1和MAGE-3的表达分别为十分之一(10%)和3%(30%)。在食道癌患者中，7例(23%)表达MAGE-1，14例(47%)表达MAGE-3，3例(10%)同时表达MAGE-1和MAGE-3。在胰腺癌中，1例(25%)表达MAGE-1，2例(50%)表达MAGE-3，1例(25%)同时表达MAGE-1和MAGE-3。经Western印迹分析，除1例乳腺癌外，其余基因均被翻译成相应的蛋白。肿瘤同时表达MAGE-1和MAGE-3的食道癌患者的生存率明显好于其他患者。为了为主动特异性免疫治疗的临床应用做准备，我们使用了一例食道癌患者的材料进行实验，该患者的肿瘤表达MAGE-3。外周血淋巴细胞在人类白细胞抗原A2限制性MAGE-3诱导的树突状细胞刺激下显著增殖，而在人类白细胞抗原A1限制性多肽冲击的树突状细胞刺激下不明显增殖。适当刺激的淋巴细胞产生肿瘤坏死因子。这些淋巴细胞对人类白细胞抗原A2和MAGE-3阳性的自体癌细胞有明显的杀伤作用，对人类白细胞抗原A24/MAGE-3阳性的同种异体细胞的杀伤作用较弱。这些结果清楚地显示了利用专业抗原提呈细胞进行基于多肽的肿瘤免疫治疗的临床应用潜力。通过淋巴细胞克隆鉴定该系统中的T细胞受体谱系。

We have investigated the expression of genes of MAGE-1, MAGE-3 and HLA-A1 for 10 breast cancer, 31 esophgeal cancer and 4 pancreatic cancer patients. There was no patint who had HLA-A1. The expression of MAGE-1 and MAGE-3 was one out of ten (10%) and 3 (30%), in breast cancer patients, respectively. In esophageal cancer patients, 7 out of 31 (23%) expressed MAGE-1 and 14 (47%) did MAGE-3, while 3 (10%) had both MAGE-1 and MAGE-3. In pancreatic cancer, 1 out of 4 (25%) expressed MAGE-1 and 2 (50%) showed MAGE-3, one (25%) had both MAGE-1 and MAGE-3. These gene expression was confirmed to be translated into the corresponding protein by Western blot analysis except for one breast cancer. Survival of those esophageal cancer patients whose tumor expressed both MAGE-1 and MAGE-3 were significantly better than that of other patients. In preparation for clinical application of active specific immunotherapy, we made experiments using materials from a esophageal cancer patient who is HLA-A2 positive and whose tumor expressed MAGE-3. The patint's peripheral blood lymphocytes proliferated significantly when they were stimulated with HLA-A2 restriced MAGE-3-derived-pepitde-pulsed cultured dendritic cells while they did not proliferate in the presence of HLA-A1 restriced peptide-pulsed dentritic cells. The appropriately stimulated lymphocytes produced tumor necrotizing factor. Finally, those lymphocytes showed significant cytotoxicity against HLA-A2&MAGE-3 positive autologous cancer cell line and had less cytotoxicity against HLA-A24/MAGE-3 positive allogeneic cell line. These results clearly show the potentiality of clinical application of peptide based tumor immunotherapy using professional antigen presenting cells. To identify the repertoire of T cell receptor in this system in under progress by lymphocyte cloning.