Linehan D C, Goedegebuure P S, Peoples G E, Rogers S O, Eberlein T J
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 1995 Nov 1;155(9):4486-91.
A tumor-specific cytotoxic T lymphocyte (CTL) immune response has been well documented in melanoma, renal cell carcinoma, and ovarian cancer. Conflicting evidence exists regarding the existence of tumor-specific CTL populations in breast cancer. Tumor cells and tumor-associated lymphocytes (TAL) were isolated from the pleural effusions of six consecutive patients with metastatic breast cancer. After solid-phase anti-CD3 stimulation, TAL cultures were expanded with weekly autologous tumor stimulation and low-dose IL-2 for 3 wk. T cell populations were characterized using flow cytometric analysis and ranged from 49 to 91% CD8+, > 98% CD3+, and < 3% CD16+. Functionally, tumor-stimulated TAL showed tumor-specific recognition of autologous tumor cells (241 +/- 142 LU20/10(7)) and no detectable lysis of autologous fibroblasts, Daudi or K562. Cytotoxicity of TAL against HLA-A2+ allogeneic targets was significantly higher when compared with HLA-A2- tumor cell lines (127 +/- 76 vs 6 +/- 18 LU, p = 0.0001). This cytotoxicity against autologous and allogeneic tumor cells was blocked by anti-HLA-A2 mAb and cold HLA-A2+ targets in cold-target inhibition assays. TAL from all HLA-A2+ patients recognized GP2, a known, HER2/neu-derived tumor-associated peptide Ag that is HLA-A2 restricted. We have shown that TAL obtained from metastatic effusions of breast cancer patients contain lymphocytes that can recognize and lyse autologous and allogeneic tumor cells in a tumor-specific, HLA-A2-restricted fashion. In addition, tumor-specific TAL derived from breast cancer patients can selectively lyse HLA-A2+ pancreatic and ovarian tumor cell targets, suggesting a common HLA-A2-restricted tumor-associated Ag between these distinct epithelial cancers. Further elucidation of the cell-mediated immune response to breast cancer and the identification of shared TAA could result in the development of broadly applicable vaccine therapies for many cancers.
肿瘤特异性细胞毒性T淋巴细胞（CTL）免疫反应在黑色素瘤、肾细胞癌和卵巢癌中已有充分记载。关于乳腺癌中是否存在肿瘤特异性CTL群体，存在相互矛盾的证据。从6例连续转移性乳腺癌患者的胸腔积液中分离出肿瘤细胞和肿瘤相关淋巴细胞（TAL）。在固相抗CD3刺激后，通过每周自体肿瘤刺激和低剂量IL-2对TAL培养物进行扩增，持续3周。使用流式细胞术分析对T细胞群体进行表征，其范围为CD8 +占49%至91%，CD3 +> 98%，CD16 +< 3%。在功能上，肿瘤刺激的TAL表现出对自体肿瘤细胞的肿瘤特异性识别（241±142 LU20/10⁷），并且未检测到对自体成纤维细胞、Daudi或K562的裂解。与HLA - A2⁻肿瘤细胞系相比，TAL对HLA - A2⁺同种异体靶标的细胞毒性显著更高（127±76对6±18 LU，p = 0.0001）。在冷靶抑制试验中，针对自体和同种异体肿瘤细胞的这种细胞毒性被抗HLA - A2单克隆抗体和冷HLA - A2⁺靶标阻断。来自所有HLA - A2⁺患者的TAL识别GP2，一种已知的、HER2/neu衍生的肿瘤相关肽抗原，其受HLA - A2限制。我们已经表明，从乳腺癌患者的转移性胸腔积液中获得的TAL含有能够以肿瘤特异性、HLA - A2限制的方式识别和裂解自体和同种异体肿瘤细胞的淋巴细胞。此外，源自乳腺癌患者的肿瘤特异性TAL可以选择性地裂解HLA - A2⁺胰腺和卵巢肿瘤细胞靶标，这表明在这些不同的上皮癌之间存在共同的HLA - A2限制的肿瘤相关抗原。进一步阐明针对乳腺癌的细胞介导免疫反应并鉴定共享的肿瘤相关抗原（TAA）可能会导致开发适用于多种癌症的广泛适用的疫苗疗法。
