HLA-A2 presents shared tumor-associated antigens derived from endogenous proteins in ovarian cancer.
HLA-A2 presents shared tumor-associated antigens derived from endogenous proteins in ovarian cancer.
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DOI：
10.4049/jimmunol.151.10.5481
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发表时间：
1993-11
影响因子：
4.4
通讯作者：
G. Peoples;P. Goedegebuure;J. Andrews;D. Schoof;T. Eberlein
中科院分区：
文献类型：
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作者：
G. Peoples;P. Goedegebuure;J. Andrews;D. Schoof;T. Eberlein
从连续六名未经治疗的卵巢癌患者中分离出来自恶性腹水的肿瘤相关淋巴细胞（TAL）和来自实体瘤的肿瘤浸润淋巴细胞（TIL）。使用固相抗 CD3、低剂量 IL-2 (50 IU/ml) 和重复肿瘤刺激，从 TAL 和 TIL 生成肿瘤特异性 CTL。使用自体肿瘤、几种同种异体卵巢肿瘤和 NK 敏感细胞系 K562 在标准细胞毒性测定中测试了 TAL 和 TIL 的特异性。抗 HLA-A-B-C mAb W6/32 用于证明这些肿瘤特异性 TAL 和 TIL 是 HLA I 类限制性的。使用 Brefeldin A 评估腹水和实体瘤通过 HLA I 类呈递 Ag 的能力，Brefeldin A 是一种真菌代谢物，可阻断病毒模型中的内源性 Ag 加工途径。 Brefeldin A 显着抑制肿瘤特异性细胞毒性以及细胞表面 HLA I 类表达，表明肿瘤相关 Ag 的内源性来源。尽管之前有关于卵巢癌抗原异质性的报道，但 HLA-A2 匹配患者（而不是不匹配对照）的显着同种异体识别证明，这种疾病中存在共享的肿瘤相关 Ag。具体来说，来自 HLA-A2+ 患者的 CTL 裂解 HLA-A2+ 同种异体靶标的能力明显优于 HLA-A2- 同种异体或 HLA-A2+ 黑色素瘤靶标。 HLA-A2-效应子则没有这种差异。此外，通过使用抗 HLA-A2 mAb BB7.2 阻断针对自体和同种异体 HLA-A2+ 靶标的 HLA-A2+ 效应子，HLA-A2 被证实是卵巢癌的主要限制元件。这些发现证实了与黑色素瘤中记录的类似的淋巴细胞/肿瘤相互作用，表明淋巴细胞识别这些人类肿瘤的共同机制。
Tumor-associated lymphocytes (TAL) from the malignant ascites and tumor-infiltrating lymphocytes (TIL) from the solid tumor were isolated from six consecutive untreated ovarian cancer patients. Tumor-specific CTL were generated from both TAL and TIL using solid phase anti-CD3, low dose IL-2 (50 IU/ml), and repeated tumor stimulation. The specificity of TAL and TIL was tested in standard cytotoxicity assays using autologous tumor, several allogeneic ovarian tumors, and the NK-sensitive cell line, K562. Anti-HLA-A-B-C mAb, W6/32, was used to demonstrate that these tumor-specific TAL and TIL were HLA class I-restricted. The ability of the ascitic and solid tumor to present Ag by HLA class I was assessed using Brefeldin A, a fungal metabolite that blocks the endogenous Ag-processing pathway in the viral model. Brefeldin A significantly inhibited tumor-specific cytotoxicity as well as HLA class I expression on the cell surface, suggesting an endogenous source of tumor-associated Ag. Despite previous reports of antigenic heterogeneity in ovarian cancer, shared tumor-associated Ag were shown to exist in this disease as demonstrated by significant allogeneic recognition of HLA-A2-matched patients as opposed to unmatched controls. Specifically, CTL from HLA-A2+ patients lysed HLA-A2+ allogeneic targets significantly better than HLA-A2- allogeneic or HLA-A2+ melanoma targets. There was no such difference with HLA-A2- effectors. Furthermore, HLA-A2 was confirmed to be a major restriction element in ovarian cancer by the blocking of HLA-A2+ effectors against both autologous and allogeneic HLA-A2+ targets with the anti-HLA-A2 mAb, BB7.2. These findings verify a similar lymphocyte/tumor interaction as has been documented in melanoma, suggesting a common mechanism of recognition of these human tumors by lymphocytes.