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

Abstract

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 γδT cells and sensitize tumors to γδT cell-mediated killing. To investigate the feasibility of γδT cell-based immunotherapy for patients with GBM, we focused on the killing of GBM cell lines by γδT 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 γδT cells were enriched in the expanded cells by the immunomagnetic depletion of αβT cells. Gliomas are resistant to NK cells but susceptible to lymphokine-activated killer cells and some cytotoxic T lymphocytes. When the γδT 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 γδT 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 γδ is crucial for the recognition of ZOL-treated GBM cells by γδT cells. Since the low level killing of GBM cells by the γδT cells was enhanced by ZOL, γδT cell-targeting therapy in combination with ZOL treatment could be effective for patients with GBM.

Enhanced Anti-Tumor Effect of Zoledronic Acid Combined with Temozolomide against Human Malignant Glioma Cell Expressing O6-Methylguanine DNA Methyltransferase

“…On the other hand, ZOL has been shown to induce a significant expansion of γδ T cells, both in vitro and in vivo [12]. As opposed to antigen-recognition by conventional αβ T cells, γδ T cell-specific antigens do not need to be processed by professional antigen-presenting cells, do not require binding presentation by classical major histocompatibility complex (MHC) molecules and are therefore able to exert potent MHC-unrestricted cytotoxic effector activity toward various tumour cells including GBM [27], [28]. Although there is a main limitation investigating the anti-cancer mechanisms of ZOL i n vivo , since the use of immunosuppressed animals do not take into account the role of the immune system and the possible involvement of ZOL in the stimulation of an immune response, combination of ZOL could be a potent approach in anti-glioma therapy.…”

Stereotaxic administrations of allogeneic human Vγ9Vδ2 T cells efficiently control the development of human glioblastoma brain tumors

“…18 Moreover, NBP-treated human glioma tumor cells are efficiently recognized by Vg9Vd2 T cells 19,20 illustrating the practicality of using human gd T cells as an attractive tool for immunotherapies of GBM. In this study, we have investigated the feasibility and the antitumor efficacy of local allogeneic Vg9Vd2 T cell immunotherapies in murine models of orthotopic human GBM tumors using commercial cell line (U-87MG) and highly infiltrative primary GBM cells (GBM-10).…”

Resistance to cytotoxicity and sustained release of interleukin-6 and interleukin-8 in the presence of decreased interferon-γ after differentiation of glioblastoma by human natural killer cells

“…Recently, T cell-based immunotherapy failed to reveal a sufficient clinical benefit, perhaps because of a decreased MHC-I expression on GBM cells [11, 12]. NK cells are prime candidates for targeting and lysing tumor cells with no or lower MHC-I expression.…”