Tuttle T M, Anderson B W, Thompson W E, Lee J E, Sahin A, Smith T L, Grabstein K H, Wharton J T, Ioannides C G, Murray J L
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Clin Cancer Res. 1998 Aug;4(8):2015-24.
Previous studies have characterized the reactivity of CD8+ CTLs with ovarian and breast cancer. There is little information about the antigens and epitopes recognized by CD4+ T cells in these patients. In this study, we analyzed the ability of T cells from peripheral blood mononuclear cells of breast cancer patients to recognize HER-2/neu (HER-2) peptides. We found that 13 of 18 patients responded by proliferation to at least one of the HER-2 peptides tested. Of these peptides, one designated G89 (HER-2: 777-789) was recognized by T cells from 10 patients. Seven of nine responding patients were HLA-DR4+, suggesting that this peptide is recognized preferentially in association with HLA-DR4. Analysis of the specificity and restriction of the cytokine responses to G89 by G89-stimulated T cells revealed that these cells secreted significantly higher levels of IFN-gamma than interleukin 4 and interleukin 10, suggesting priming for a Th0-T helper 1 response. The same pattern of cytokine responses was observed to the intracellular domain of HER-2 protein, suggesting that G89-stimulated T cells recognized epitopes of the HER-2 protein in association with HLA-DR4. Because HLA-DR4 is present in 25% of humans, characterization of MHC class II-restricted epitopes inducing Th0-T helper 1 responses may provide a basis for the development of multivalent HER-2-based vaccines against breast and ovarian cancer.
先前的研究已经对CD8+细胞毒性T淋巴细胞（CTL）与卵巢癌和乳腺癌的反应性进行了表征。关于这些患者中CD4+ T细胞识别的抗原和表位的信息很少。在本研究中，我们分析了乳腺癌患者外周血单个核细胞中的T细胞识别HER-2/neu（HER-2）肽的能力。我们发现，18名患者中有13名对至少一种所测试的HER-2肽有增殖反应。在这些肽中，一种命名为G89（HER-2：777-789）的肽被10名患者的T细胞识别。9名有反应的患者中有7名是HLA-DR4阳性，这表明该肽优先与HLA-DR4结合被识别。对G89刺激的T细胞对G89的细胞因子反应的特异性和限制性分析显示，这些细胞分泌的γ干扰素水平明显高于白细胞介素4和白细胞介素10，这表明引发了Th0 - T辅助1型反应。对HER-2蛋白的细胞内结构域也观察到相同的细胞因子反应模式，这表明G89刺激的T细胞识别与HLA-DR4结合的HER-2蛋白表位。由于25%的人存在HLA-DR4，对诱导Th0 - T辅助1型反应的MHC II类限制性表位的表征可能为开发针对乳腺癌和卵巢癌的多价HER-2疫苗提供基础。
