Adoptive immunotherapy for pancreatic cancer: cytotoxic T lymphocytes stimulated by the MUC1-expressing human pancreatic cancer cell line YPK-1.
Adoptive immunotherapy for pancreatic cancer: cytotoxic T lymphocytes stimulated by the MUC1-expressing human pancreatic cancer cell line YPK-1.
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DOI：
10.3892/or.20.1.155
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发表时间：
2008-07
期刊：
影响因子：
4.2
通讯作者：
Toru Kawaoka;M. Oka;M. Takashima;T. Ueno;Koutaro Yamamoto;N. Yahara;S. Yoshino;S. Hazama
中科院分区：
文献类型：
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作者：
Toru Kawaoka;M. Oka;M. Takashima;T. Ueno;Koutaro Yamamoto;N. Yahara;S. Yoshino;S. Hazama
MUC 1是一种肿瘤相关抗原，在胰腺浸润性导管癌（PC）中过表达。MUC 1特异性细胞毒性T淋巴细胞（CTL）以HLA非限制性方式识别MUC 1分子。在这项研究中，我们进行了过继免疫治疗（AIT）与PC患者的CTL刺激的MUC 1表达的人PC细胞系YPK-1。为了诱导CTL，将外周血单核细胞（PBMC）与灭活的YPK-1细胞一起培养3天，然后用白细胞介素（IL）-2刺激7天。分析了这些细胞对人癌细胞系的细胞毒性，并评价了各种抗体抑制细胞毒性的能力。我们对8例不能切除的PC和20例可切除的PC进行了手术治疗。如上所述诱导CTL，悬浮于100 ml盐水中并静脉内注射。诱导的CTL对5个MUC 1表达PC细胞系和乳腺癌细胞系具有细胞毒性，无论HLA表型如何。在7个MUC 1阴性癌细胞系中观察到低细胞毒性。抗CD 3单克隆抗体（mAb）或抗CD 8 mAb强烈抑制对YPK-1的细胞毒性，而抗I类mAb显示无抑制作用。与抗MUC 1 mAb孵育的YPK-1细胞也显示出低细胞毒性。临床上，AIT治疗不能切除的PC患者的中位生存时间为5.0个月。无肝转移的5例患者均无肝复发。20例可切除的PC中18例接受根治性手术，中位生存时间为17.8个月，术后1、2和3年生存率分别为83.3%、32.4%和19.4%。肝转移仅1例，未见副作用。由MUC 1表达的人胰腺癌细胞系刺激的CTL以MUC 1特异性和MHC不受限制的方式显示出强的肿瘤细胞毒活性。AIT与刺激的CTL显着抑制PC术后肝复发。CTL的辅助免疫治疗可能有助于PC的术后治疗。
MUC1 is a tumor-associated antigen that is overexpressed in invasive ductal carcinomas of the pancreas (PC). MUC1-specific cytotoxic T lymphocytes (CTLs) recognize MUC1 molecules in a HLA-unrestricted manner. In this study, we performed adoptive immunotherapy (AIT) in patients with PC with CTLs stimulated by the MUC1-expressing human PC cell line YPK-1. To induce CTLs, peripheral blood mononuclear cells (PBMCs) were cultured for 3 days with inactivated YPK-1 cells and then stimulated with interleukin (IL)-2 for 7 days. The cytotoxicity of these cells against human cancer cell lines was analyzed, and a variety of antibodies were evaluated for their ability to inhibit cytotoxicity. We treated 8 patients with unresectable PC and 20 patients with resectable PC postsurgically. CTLs were induced as described above, suspended in 100 ml saline and injected intravenously. Induced CTLs were cytotoxic against 5 MUC1-expressing PC cell lines and a breast cancer cell line, regardless of the HLA phenotype. Low cytotoxicity was observed in 7 MUC1-negative cancer cell lines. Anti-CD3 monoclonal antibody (mAb) or anti-CD8 mAb strongly inhibited cytotoxicity against YPK-1, whereas anti-class I mAb showed no inhibition. YPK-1 cells incubated with anti-MUC1 mAb also showed low cytotoxicity. Clinically, the median survival time was 5.0 months for patients with unresectable PC treated with AIT. None of the 5 patients without liver metastasis showed hepatic recurrence. The median survival time was 17.8 months for 18 out of 20 patients with resectable PC who underwent curative surgery, and the 1-, 2- and 3-year survival rates after surgery were 83.3, 32.4, and 19.4%, respectively. Liver metastasis was found in only one patient and no side effects of AIT were observed. CTLs stimulated by a MUC1-expressing human pancreatic cancer cell line showed a strong tumor cytotoxic activity in a MUC1-specific and MHC-unrestricted manner. AIT with stimulated CTLs significantly suppressed the postsurgical hepatic recurrence of PC. Adjuvant immunotherapy with CTLs may be useful in the postsurgical treatment of PC.