title: Trastuzumab enhanced the cytotoxicity of Vγ9Vδ2 T cells against zoledronate-sensitized osteosarcoma cells.
abstract: Preliminary studies of Vγ9Vδ2 T cells and zoledronate (ZOL) present promising reasons to exploit their immunotherapeutic potential for osteosarcoma treatment (OS). ZOL is a third-generation aminobisphosphonate (ABP) and is well established in the management of cancer-induced bone disease. However, ZOL is characterized by high tropism for bone matrix, and the efficacy of ZOL for sensitizing tumors remains to be optimized. Vγ9Vδ2 T cells are important effectors of antibody-dependent cell-mediated cytotoxicity (ADCC). In this study, we investigated whether Vγ9Vδ2 T cell-mediated killing of ZOL-pretreated OS cells could be increased by the anti-HER-2 monoclonal antibody trastuzumab (TTZ). The cytotoxic activity of Vγ9Vδ2 T cells against osteosarcoma was assessed by an MTS assay in the presence or absence of TTZ. A CD107a assay was used to measure degranulation in cytotoxic Vγ9Vδ2 T cells. Blocking studies were used to determine the effect of relative ligands on Vγ9Vδ2 T cell recognition. TTZ induced an ADCC response in the OS cell line, U2OS; however, it had no effect on another OS cell line HOS with low levels of surface HER2 expression. Although the OS cells pretreated with ZOL for clinically relevant time periods (2hours) stimulated a suboptimal immune response of Vγ9Vδ2 T cells, TTZ could further enhance the cytotoxicity of Vγ9Vδ2 T cells. These results demonstrate that combining TTZ and ZOL significantly increases the cytotoxic potential of Vγ9Vδ2 T cells. This study raises the possibility of utilizing ZOL and TTZ in Vγ9Vδ2 T cell-based immunotherapy for OS.
authors.affiliation: Department of Orthopedics, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. Electronic address: liumeng80@163.com.
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Orthopedics, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. Electronic address: mynameissll@163.com.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Sun
authors.affiliation: Department of Epidemiology and Health Statistics, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. Electronic address: yingjunguqing2006@126.com.
authors.forename: Ying-Jun
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Orthopedics, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. Electronic address: hengyuanxiang2001@163.com.
authors.forename: Heng-Yuan
authors.initials: HY
authors.lastname: Li
authors.affiliation: Department of Orthopedics, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. Electronic address: idealfly2001@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. Electronic address: libinghaozj2001@163.com.
authors.forename: Bing-Hao
authors.initials: BH
authors.lastname: Li
authors.affiliation: Department of Orthopedics, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, P.R. China. Electronic address: yezhaoming123@gmail.com.
authors.forename: Zhao-Ming
authors.initials: ZM
authors.lastname: Ye
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000473:pathology*; D015550:Cell Degranulation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D012516:Osteosarcoma / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects*; D000068878:Trastuzumab / Q000494:pharmacology*; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D000077211:Zoledronic Acid; C508053:ERBB2 protein, human
keywords: ADCC; Monoclonal antibodies; Osteosarcoma; Trastuzumab; Vγ9Vδ2 T cells; Zoledronate