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Zoledronic acid-induced expansion of γδ T cells from early-stage breast cancer patients: effect of IL-18 on helper NK cells

Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Human γδ T cells display potent cytotoxicity against various tumor cells pretreated with zoledronic acid (Zol). Zol has shown benefits when added to adjuvant endocrine therapy for patients with early-stage breast cancer or to standard chemotherapy for patients with multiple myeloma. Although γδ T cells may contribute to this additive effect, the responsiveness of γδ T cells from early-stage breast cancer patients has not been fully investigated. In this study, we determined the number, frequency, and responsiveness of Vγ2Vδ2 T cells from early- and late-stage breast cancer patients and examined the effect of IL-18 on their ex vivo expansion. The responsiveness of Vγ2Vδ2 T cells from patients with low frequencies of Vγ2Vδ2 T cells was significantly diminished. IL-18, however, enhanced ex vivo proliferative responses of Vγ2Vδ2 T cells and helper NK cells from patients with either low or high frequencies of Vγ2Vδ2 T cells. Treatment of breast cancer patients with Zol alone decreased the number of Vγ2Vδ2 T cells and reduced their ex vivo responsiveness. These results demonstrate that Zol can elicit immunological responses by γδ T cells from early-stage breast cancer patients, but that frequent in vivo treatment reduces Vγ2Vδ2 T cell numbers and their responsiveness to stimulation.

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Acknowledgments

We are grateful to Ms. Chiyomi Inoue for excellent technical assistance and to GlaxoSmithKline plc (Research Triangle Park, NC) and Shionogi Pharmaceutical Co., Ltd. (Chuo-ku, Osaka, Japan) for providing recombinant human IL-18 and IL-2, respectively. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Culture, Sports, and Technology of Japan (MEXT) (to Y. T.), by “Coordination, Support, and Training Program for Translational Research” from MEXT (to Y. T., N. M., T. S., and M. T.), by “Special Coordination Funds for Promoting Science and Technology” from MEXT and Astellas Pharma Inc. through the “Formation of Center for Innovation by Fusion of Advanced Technologies” program (to Y. T.), by “Platform for Drug Discovery, Informatics, and Structural Life Science” from MEXT (to Y. T.), and by grants from the National Institute of Arthritis and Musculoskeltal and Skin Disease, National Institutes of Health (AR045504), National Cancer Institute, National Institutes of Health (CA113874), and the Department of Veterans Affairs (BX000972) (to C. T. M.).

Conflict of interest

C. T. M. is a co-inventor of US Patent 8,012,466 on the development of live bacterial vaccines for activating γδ T cells. The other authors declare that they have no financial or commercial conflict of interest.

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Correspondence to Yoshimasa Tanaka.

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Tomoharu Sugie and Kaoru Murata-Hirai contributed equally to this work.

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Sugie, T., Murata-Hirai, K., Iwasaki, M. et al. Zoledronic acid-induced expansion of γδ T cells from early-stage breast cancer patients: effect of IL-18 on helper NK cells. Cancer Immunol Immunother 62, 677–687 (2013). https://doi.org/10.1007/s00262-012-1368-4

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