Yoshino I, Peoples G E, Goedegebuure P S, Maziarz R, Eberlein T J
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
J Immunol. 1994 Mar 1;152(5):2393-400.
To study potential sources of tumor-associated Ags in human ovarian cancer, we have established two ovarian tumor cell lines (OvS1 and OvA2) from two ovarian cancer patients, which express the cellular oncogene HER2/neu. Corresponding tumor infiltrating lymphocyte cultures have also been established and display an autologous tumor-specific pattern of cytotoxicity that is HLA-A2 restricted. To determine the potential relationship between HER2/neu expression and CTL-mediated cytolysis, we first established tumor cell clones from OvS1. These were categorized as high or low expressors of HER2/neu (cOvS1+ or cOvS1-, respectively), and cOvS1+ clones displayed a significantly higher sensitivity to CTL killing as compared with cOvS1- clones. To modulate the expression of HER2/neu, ovarian cancer cells were treated with IFN-gamma. After this exposure, HER2/neu expression was significantly decreased, whereas the expression of HLA Class I was significantly increased. Despite the increase in HLA Class I molecules on the cell surface, CTL-mediated cytolysis of both OvS1 and OvA2 was significantly decreased. IFN-gamma treated cOvS1+ clones displayed a similar decrease in sensitivity to CTL killing, whereas IFN-gamma treated cOvS1- clones displayed an increase or no change in sensitivity to CTL. To confirm this apparent association between HER2/neu expression and CTL recognition, melanoma tumor cell lines that were insensitive to ovarian tumor-specific CTL were transfected with the HER2/neu gene. An HLA-A2+ HER2/neu-transfected melanoma cell line was made sensitive to HLA-A2 restricted ovarian tumor-specific CTL but not to HLA-A2 unrestricted CTL, whereas an HLA-A2- HER2/neu-transfected melanoma remained insensitive to HLA-A2 restricted CTL. These results demonstrate that the sensitivity of ovarian epithelial tumor cells to CTL-mediated lysis is associated with the level of expression of HER2/neu, suggesting that this oncogene product may serve as a source of tumor-associated Ags or as an inducer of such peptides. This is the first time in a human tumor system that oncogene expression has been related to the induction of antigenicity. These results prompt us to approach new strategies for immunotherapy of cancer.
为研究人类卵巢癌中肿瘤相关抗原的潜在来源，我们从两名卵巢癌患者身上建立了两个卵巢肿瘤细胞系（OvS1和OvA2），它们表达细胞癌基因HER2/neu。还建立了相应的肿瘤浸润淋巴细胞培养物，其显示出一种HLA - A2限制性的自体肿瘤特异性细胞毒性模式。为确定HER2/neu表达与CTL介导的细胞溶解之间的潜在关系，我们首先从OvS1建立了肿瘤细胞克隆。这些克隆被分类为HER2/neu的高表达或低表达（分别为cOvS1+或cOvS1-），与cOvS1-克隆相比，cOvS1+克隆对CTL杀伤表现出显著更高的敏感性。为调节HER2/neu的表达，用γ干扰素处理卵巢癌细胞。暴露后，HER2/neu表达显著降低，而HLA I类分子的表达显著增加。尽管细胞表面HLA I类分子增加，但OvS1和OvA2的CTL介导的细胞溶解均显著降低。γ干扰素处理的cOvS1+克隆对CTL杀伤的敏感性有类似降低，而γ干扰素处理的cOvS-克隆对CTL的敏感性增加或无变化。为证实HER2/neu表达与CTL识别之间的这种明显关联，对卵巢肿瘤特异性CTL不敏感的黑色素瘤肿瘤细胞系用HER基因进行转染。一个HLA - A2+ HER2/neu转染的黑色素瘤细胞系对HLA - A2限制性卵巢肿瘤特异性CTL敏感，但对HLA - A2非限制性CTL不敏感，而一个HLA - A2- HER2/neu转染黑色素瘤对HLA - A2限制性CTL仍不敏感。这些结果表明卵巢上皮肿瘤细胞对CTL介导的裂解的敏感性与HER2/neu的表达水平相关，提示这种癌基因产物可能作为肿瘤相关抗原的来源或此类肽的诱导剂。这是人类肿瘤系统中首次癌基因表达与抗原性诱导相关。这些结果促使我们探索癌症免疫治疗的新策略。
