Zoledronate Enhances the Cytotoxicity of Gamma Delta T Cell Immunotherapy in an Orthotopic Mouse Model of Osteolytic Osteosarcoma
Date
2018
Authors
Zysk, A.
DeNichilo, M.
Zinonos, I.
Hay, S.
Liapis, V.
Ponomarev, V.
Zannettino, A.
Evdokiou, A.
Panagopoulos, V.
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Journal article
Citation
Journal of Cancer Science and Therapy, 2018; 10(9):262-266
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Abstract
ct
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 osteolys
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Copyright 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.