Activation by zoledoronic acid and IL-18 of γδ T cells from early-stage breast cancer patients in the context of helper NK cells.

e21004 Background: 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. Methods: Breast cancer patients (n=80) were enrolled after institutional review board approval and with written informed consent. Peripheral blood mononuclear cells (PBMC) were purified and stimulated with Zol/IL-2 or Zol/IL-2/IL-18 for 2 to 10 days. The expanded cells were assessed on flow cytometry and the production of IFN-γ and TNF-α measured through ELISA. Results: 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 Vγ2Vδ2T cells and helper NK cells (CD3-CD56brightCD11c+CD14-CD16+NKGD2+NKp44low) from patients with either low or high frequencies of Vγ2Vδ2 T cells. Cell-to-cell contact between γδ T and helper NK cells appeared to promote expansion of γδ T cells. Exogenous IL-18 markedly enhanced IFN-γ and TNF-α production from PBMC stimulated by Zol/IL-2, whereas the addition of an anti-IL-18Rα mAb reduced cytokine production. Conclusions: These results demonstrate that Zol elicits immunological responses by γδ T cells from early-stage breast cancer patients and IL-18 enhances proliferative responses and effector functions of γδ T cells in the context of helper NK cells.