Zysk, A.DeNichilo, M.Zinonos, I.Hay, S.Liapis, V.Ponomarev, V.Zannettino, A.Evdokiou, A.Panagopoulos, V.2025-12-182025-12-182018Journal of Cancer Science and Therapy, 2018; 10(9):262-2661948-59561948-5956https://hdl.handle.net/11541.2/41807ct Objective: Osteosarcoma is the most common primary tumor of the bone, predominantly affecting children and adolescents. While localized osteosarcoma can be readily treated with the use of pre-operative chemotherapy in combination with surgery, patients who develop metastatic disease and tumor-induced osteolysis continue to have a poor prognosis. Many cancer cells express tumor-specific antigens, rendering them vulnerable to immune effector T cell killing. There is increasing evidence that highly cytotoxic gamma delta (Vγ9Vδ2) T cells together with the bone anti-resorptive drug zoledronate may hold significant clinical benefit in the treatment of a variety of tumor types. Methods: Ex vivo expanded Vγ9Vδ2 T cells were used to assess effector-mediated killing of osteosarcoma cells (BTK-143 and K-HOS) in response to zoledronate pre-treatment. An orthotopic mouse model of osteolytic osteosarcoma was used to verify Vγ9Vδ2 T cell cytotoxicity in combination with zoledronate on tumor growth, osteolysis and metastasis. Results: Pre-treatment of osteosarcoma cells with zoledronate enhanced Vγ9Vδ2 T cell rapid killing compared to untreated cells in vitro via blockade of the mevalonate pathway. When adoptively transferred into osteosarcoma bearing NOD/SCID mice in vivo, Vγ9Vδ2 T cells in combination with zoledronate potentiated the anti-cancer efficacy of Vγ9Vδ2T cells and inhibited tumor induced osteolysis. Importantly, Vγ9Vδ2 T cells alone reduced both the incidence and burden of lung metastases. Conclusion: This study demonstrated the dual-action of zoledronate to enhance the immunogenicity of osteosarcoma cells to Vγ9Vδ2 T cell cytotoxicity and provide protection against tumor-induced osteolysenCopyright 2018 Zysk A, et al. This is an open-access article distributed under the terms of the creative common attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.gamma delta T cellimmunotherapyosteolysisosteosarcomazoledronteJournal article10.4172/1948-5956.1000554Zysk, A. [0000-0003-0901-1542]Liapis, V. [0000-0002-2354-3521]Zannettino, A. [0000-0002-6646-6167]Evdokiou, A. [0000-0001-8321-9806]Panagopoulos, V. [0000-0002-6879-1262]