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Front. Immunol. | doi: 10.3389/fimmu.2018.00377

Valproic acid combined with zoledronate enhance γδ T cell-mediated cytotoxicity against osteosarcoma cells via the accumulation of mevalonate pathway intermediates

 Shengdong Wang1,  Hengyuan Li1, Chenyi Ye1, Peng Lin1,  Binghao Li1, Wei Zhang1, Lingling Sun1,  Zhan Wang1, Deting Xue1, Wangsiyuan Teng1, Xingzhi Zhou1, Nong Lin1 and  Ye Zhaoming1*
  • 1Department of Orthopaedics, Second Affiliated Hospital of Zhejiang University School of Medicine, China

The long term survival of osteosarcoma has remained unchanged in the last several decades. Immunotherapy is proved to be a promising therapeutic strategy against osteosarcoma, especially for those with metastasis. Our previous study explored the sensibilization of zoledronate (ZOL) in γδ T cell-mediated cytotoxicity against osteosarcoma, but we haven’t yet elucidated the specific mechanism. Besides, high concentration is required to achieve these effects, whereas plasma ZOL concentration declines rapidly in the circulation. Valproic acid (VPA), a histone deacetylase inhibitor (HDAC-I) commonly used as the antiepileptic drug, has attracted much attention due to its synergistic antitumor efficacy with chemotherapy or immunotherapy. Here, we demonstrated that VPA combined with ZOL revealed the synergistic effect in enhancing antitumor efficacy of γδ T cells against osteosarcoma cells. This enhancement was mainly TCR-mediated and largely dependent on granule exocytose pathway. Of note, our findings indicated that ZOL sensitized osteosarcoma cells to γδ T cells by increasing the accumulation of the mevalonate pathway intermediates, which could be facilitated by VPA. We also found that this combination had similar effects on primary osteosarcoma cells. All the results suggested that VPA combined with ZOL could reduce the dose required to achieve a significant anti-tumor effect of γδ T cells, promoting it to be a novel therapy against osteosarcoma.

Keywords: γδ T cells, Zoledronate, HDAC-I, Osteosarcoma, Mevalonate pathway intermediates, Synergism

Received: 25 Nov 2017; Accepted: 12 Feb 2018.

Edited by:

Rayne Rouce, Baylor College of Medicine, United States

Reviewed by:

Daniel Olive, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Dr. Kawaljit Kaur, University of California, Los Angeles, United States  

Copyright: © 2018 Wang, Li, Ye, Lin, Li, Zhang, Sun, Wang, Xue, Teng, Zhou, Lin and Zhaoming. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Ye Zhaoming, ZHAOMING., Second Affiliated Hospital of Zhejiang University School of Medicine, Department of Orthopaedics, No.88, Jiefang Road, Hangzhou, 310009, Zhejiang, China,