Tumor-specific and HLA-A2-restricted cytolysis by tumor-associated lymphocytes in human metastatic breast cancer

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 LU₂₀/10⁷) 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.