Cytotoxic human peripheral blood-derived γδT cells kill glioblastoma cell lines: implications for cell-based immunotherapy for patients with glioblastoma

Glioblastoma (GBM) is a highly aggressive brain tumor for which novel therapeutic approaches, such as immunotherapy, are urgently needed. Zoledronate (ZOL), an inhibitor of osteoclastic activity, is known to stimulate peripheral blood-derived gamma delta T cells and sensitize tumors to gamma delta T cell-mediated killing. To investigate the feasibility of gamma delta T cell-based immunotherapy for patients with GBM, we focused on the killing of GBM cell lines by gamma delta T cells and the molecular mechanisms involved in these cell-cell interactions. Peripheral blood mononuclear cells were expanded in ZOL and interleukin (IL)-2 for 14 days, and gamma delta T cells were enriched in the expanded cells by the immunomagnetic depletion of alpha beta T cells. Gliomas are resistant to NK cells but susceptible to lymphokine-activated killer cells and some cytotoxic T lymphocytes. When the gamma delta T cell-mediated killing of three GBM cell lines (U87MG, U138MG and A172 cells) and an NK-sensitive leukemia cell line (K562 cells) were tested, 32 % U87MG, 15 % U138MG, 1 % A172, and 50 % K562 cells were killed at an effector: target ratio of 5:1. The gamma delta T cell-mediated killing of all three GBM cell lines was significantly enhanced by ZOL and this ZOL-enhanced killing was blocked by an anti-T cell receptor (TcR) antibody. These results indicated that TcR gamma delta is crucial for the recognition of ZOL-treated GBM cells by gamma delta T cells. Since the low level killing of GBM cells by the gamma delta T cells was enhanced by ZOL, gamma delta T cell-targeting therapy in combination with ZOL treatment could be effective for patients with GBM.