Interleukin-15 Enhances Lysis of Autologous and Allogeneic Human Pancreatic Cancer Cells by Cytotoxic T-Lymphocytes In Vitro
Abstracts
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Background. Interleukin-15 shares no homology with IL-2, but requires parts of the IL-2 receptor complex for binding and signaling. Its possible role for use in novel immunotherapy approaches remains unclear. This study was performed to evaluate the influence of IL-15 on tumor-specific CTL and LAK cells in pancreatic cancer. Methods. LAK cells were generated from buffy coats and high-dose rhIL-2, while CTL were generated from HLA-A2 positiv tumor-associated lymphocytes, activated on anti-CD3, educated using repeated autologous tumor cell stimulation. Prior to functional assays using the LDH-method, CTL and LAK cells were incubated with IL-15 (3-100ng/ml) for 1-3 days. Target cells were autologous and allogeneic pancreatic cancer cells with/without mAB anti-HLA I (W6/32) or mAB anti-HLA-A2 (BB7.2). Results. Allogeneic LAK cells lysed pancreatic cancer cells to a high amount (>55% at 40:1 target/effector ratio (T/R), the lysis was not HLA-A2 restricted (P>0.05). Incubation with IL-15 did not enhance or lower cytotoxicity in LAK cells. TAL-derived CTL lysed autologous and allogeneic tumor cells HLA-A2 restricted with a median of 42% at 40:1 T/R for HLA-A2 positiv and 17% for HLA-A2 negativ, resp (P<0.001). Incubation with IL-15 enhanced lysis of autologous tumor cells time- and dose-dependent (P<0.05). Lysis of autologous tumor cells was significant higher than of allogeneic tumor cells (P<0.05). Lysis was inhibited in all experiments by incubation with mAB anti-HLA I (P<0.05) and -A2 (P<0.05). Our data demonstrate that there is a different influence of IL-15 on HLA-A2-restricted and tumor-specific CTL vs LAK cells. Further studies on the functional role of IL-15 are neccessary to evaluate its distinct mechanisms of action. |
