Peoples G E, Yoshino I, Douville C C, Andrews J V, Goedegebuure P S, Eberlein T J
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
J Immunol. 1994 May 15;152(10):4993-9.
We have recently shown that HLA-A2-restricted, tumor-specific CTL can be isolated from tumor-infiltrating lymphocytes (TIL) in ovarian cancer, and that the sensitivity of ovarian tumors to these CTL is correlated with HER2/neu expression. Furthermore, utilizing PCR, we have documented previously that V beta 2, V beta 3, V beta 6, and V beta 7 are represented in increased proportions in ovarian tumor-specific CTL lines. Therefore, to correlate the interaction of these specific TCR V beta segments with the HLA-A2 molecule and potential tumor-associated Ags (TAA) related to HER2/neu expression, we have utilized available mAbs to V beta 2, V beta 3, and V beta 6. We found that V beta 2+, V beta 3+, and V beta 6+ CTL mediate antitumor activity, and a combination of these mAbs resulted in 83 to 95% inhibition of the cytotoxicity against autologous tumor from three separate patients. These mAbs also were capable of blocking HLA-A2-matched allogeneic cytotoxicity, suggesting that all three V beta families recognize TAA in the context of HLA-A2. An HLA-A2+ melanoma was transfected with the HER2/neu gene and became sensitive to HLA-A2+ ovarian cancer-specific CTL lysis. This cytotoxicity was mediated by V beta 3+ and V beta 6+ CTL, as demonstrated by mAb-blocking studies. FACS-depletion studies confirmed that CTL populations depleted of V beta 3 or V beta 6 no longer could recognize the HER2/neu transfectant. We conclude that V beta 3 and V beta 6 recognize some TAA that are either derived from the HER2/neu protein or induced by the expression of the HER2/neu gene and presented in the context of HLA-A2. Furthermore, V beta 2 seems to recognize an HER2/neu-unrelated Ag system also presented by HLA-A2.
我们最近发现，可从卵巢癌的肿瘤浸润淋巴细胞（TIL）中分离出HLA - A2限制性、肿瘤特异性CTL，并且卵巢肿瘤对这些CTL的敏感性与HER2/neu表达相关。此外，利用PCR技术，我们先前已证明Vβ2、Vβ3、Vβ6和Vβ7在卵巢肿瘤特异性CTL系中的比例增加。因此，为了关联这些特定TCR Vβ片段与HLA - A2分子以及与HER2/neu表达相关的潜在肿瘤相关抗原（TAA）之间的相互作用，我们使用了针对Vβ2、Vβ3和Vβ6的可用单克隆抗体。我们发现Vβ2 +、Vβ3 +和Vβ6 + CTL介导抗肿瘤活性，这些单克隆抗体的组合导致对来自三名不同患者的自体肿瘤的细胞毒性抑制率达到83%至95%。这些单克隆抗体也能够阻断HLA - A2匹配的同种异体细胞毒性，表明所有这三个Vβ家族在HLA - A2的背景下识别TAA。一个HLA - A2 +黑色素瘤转染了HER2/neu基因后，对HLA - A2 +卵巢癌特异性CTL裂解变得敏感。如单克隆抗体阻断研究所证明的，这种细胞毒性由Vβ3 +和Vβ6 + CTL介导。荧光激活细胞分选（FACS）去除研究证实，去除Vβ3或Vβ6的CTL群体不再能够识别HER2/neu转染体。我们得出结论，Vβ3和Vβ6识别一些要么源自HER2/neu蛋白，要么由HER2/neu基因表达诱导并在HLA - A2背景下呈递的TAA。此外，Vβ2似乎识别一种也由HLA - A2呈递的与HER2/neu无关的抗原系统。
