Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Hum Immunol. 2012 Jan;73(1):11-6. doi: 10.1016/j.humimm.2011.10.017. Epub 2011 Oct 23.
Human breast cancer-associated antigen, mammaglobin-A (Mam-A), potentially offers a novel therapeutic target as a breast cancer vaccine. In this study, we define the CD8(+) cytotoxic T lymphocyte (CTL) response to Mam-A-derived candidate epitopes presented in the context of HLA-A24 (A*2402). HLA-A24 has a frequency of 72% in Japanese, 27% in Asian Indian, and 18% in Caucasian populations. Using a human leukocyte antigen (HLA)-binding prediction algorithm we identified 7 HLA-A24-restricted Mam-A-derived candidate epitopes (MAA24.1-7). Membrane stabilization studies with TAP-deficient T2 cells transfected with HLA-A2402 (T2.A24) indicated that MAA24.2 (CYAGSGCPL) and MAA24.4 (ETLSNVEVF) have the highest HLA-A24 binding affinity. Further, 2 CD8(+) CTL cell lines generated in vitro against T2.A24 cells individually loaded with Mam-A-derived candidate epitopes demonstrated significant cytotoxic activity against MAA24.2 and MAA24.4. In addition, the same CD8(+) CTL lines lysed the HLA-A24(+)/Mam-A(+) stable transfected human breast cancer cell lines AU565 and MDA-MB-361. However, these CTLs had no cytotoxicity against HLA-A24(-)/Mam-A(+) and HLA-A24(+)/Mam-A(-) breast cancer cell lines. In summary, our results define HLA-A24-restricted, Mam-A-derived, CD8(+) CTL epitopes that can potentially be employed for Mam-A-based breast cancer vaccine therapy to breast cancer patients with HLA-A24 phenotype.
人乳腺癌相关抗原，乳球蛋白-A（Mam-A），作为一种乳腺癌疫苗，可能提供了一个新的治疗靶点。在这项研究中，我们定义了在 HLA-A24（A*2402）背景下呈现的 Mam-A 衍生候选表位的 CD8+细胞毒性 T 淋巴细胞（CTL）反应。HLA-A24 在日本人中的频率为 72%，在印度人中为 27%，在白种人中为 18%。使用人类白细胞抗原（HLA）结合预测算法，我们鉴定了 7 个 HLA-A24 限制的 Mam-A 衍生候选表位（MAA24.1-7）。用 HLA-A2402（T2.A24）转染的 TAP 缺陷 T2 细胞进行膜稳定研究表明，MAA24.2（CYAGSGCPL）和 MAA24.4（ETLSNVEVF）具有最高的 HLA-A24 结合亲和力。此外，针对单独加载 Mam-A 衍生候选表位的 T2.A24 细胞体外生成的 2 个 CD8+CTL 细胞系显示出对 MAA24.2 和 MAA24.4 的显著细胞毒性。此外，相同的 CD8+CTL 系裂解 HLA-A24(+)/Mam-A(+)稳定转染的人乳腺癌细胞系 AU565 和 MDA-MB-361。然而，这些 CTL 对 HLA-A24(-)/Mam-A(+)和 HLA-A24(+)/Mam-A(-)乳腺癌细胞系没有细胞毒性。总之，我们的结果定义了 HLA-A24 限制的 Mam-A 衍生的 CD8+CTL 表位，这些表位可用于基于 Mam-A 的乳腺癌疫苗疗法，用于具有 HLA-A24 表型的乳腺癌患者。
