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

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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.

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Acknowledgments

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 22791352).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

The study design was approved by the ethics committee at Clinic Grandsoul Nara, Uda, Japan, and conformed to the Declaration of Helsinki.

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Authors and Affiliations

  1. Department of Neurosurgery, Nara Medical University School of Medicine, 840, Shijocho, Kashihara, Nara, 634-8522, Japan

    Tsutomu Nakazawa, Mitsutoshi Nakamura, Young Soo Park, Yasushi Motoyama, Yasuo Hironaka, Fumihiko Nishimura, Ichiro Nakagawa, Shuichi Yamada, Ryosuke Matsuda, Kentaro Tamura, Tadashi Sugimoto, Yasuhiro Takeshima, Akiko Marutani & Hiroyuki Nakase

  2. Department of Pathogen, Infection and Immunity, Nara Medical University School of Medicine, Kashihara, Japan

    Yukiteru Ouji & Masahide Yoshikawa

  3. Department of Microbiology, Nara Medical University School of Medicine, Kashihara, Japan

    Noriko Ouji

  4. Clinic Grandsoul Nara, Uda, Japan

    Takahiro Tsujimura

  5. Grandsoul Research Institute for Immunology, Inc., Uda, Japan

    Tsutomu Nakazawa

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  1. Tsutomu Nakazawa
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Correspondence to Tsutomu Nakazawa.

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Nakazawa, T., Nakamura, M., Park, Y.S. et al. Cytotoxic human peripheral blood-derived γδT cells kill glioblastoma cell lines: implications for cell-based immunotherapy for patients with glioblastoma. J Neurooncol 116, 31–39 (2014). https://doi.org/10.1007/s11060-013-1258-4

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  • DOI: https://doi.org/10.1007/s11060-013-1258-4

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