Interleukin‐12 Augments the Generation of Autologous Tumor‐reactive CD8+ Cytotoxic T Lymphocytes from Tumor‐infiltrating Lymphocytes

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Abstract
Human tumor‐infiltrating lymphocytes (TIL) were obtained from breast cancer, renal cancer or neuroblastoma to investigate the generation of autologous tumor‐reactive CD8+ cytotoxic T lymphocytes (CTL). When TIL were cultured with interleukin (IL)‐2 (100 U/ml), the growth of TIL peaked around 8–10 days after the initiation of culture. In contrast, the proliferation of TIL cultured with IL‐2 plus IL‐12 peaked around 4–5 days after culture and tumor cells rapidly disappeared from the culture. To determine the generation of autologous tumor‐reactive CD8+ CTL, TIL‐derived CD8+ T cells were separated by FACStar. Both IL‐2‐activated and IL‐2 plus IL‐12‐activated TIL‐CD8+ T cells showed the same level of lymphokine‐activated killer activity against a variety of tumor cells. However, TIL‐CD8+ T cells activated with IL‐2 plus IL‐12 revealed greatly augmented cytotoxicity against autologous tumor cells compared with that induced by IL‐2 alone. The autologous tumor cell‐killing activity of TIL‐CD8+ CTL was significantly inhibited by the addition of F(ab)2 anti‐CD3 monoclonal antibody, indicating that these CTL recognize autologous tumor antigen through T cell receptor. These results imply that IL‐12 is a novel cytokine which facilitates the generation of autologous tumor‐reactive CD8+ CTL from TIL.