Valproic Acid Combined with Zoledronate Enhance γδ T Cell-Mediated Cytotoxicity against Osteosarcoma Cells via the Accumulation of Mevalonate Pathway Intermediates

Abstract

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 have not 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 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 antitumor effect of γδ T cells, promoting it to be a novel therapy against osteosarcoma.

Cancer immunotherapy with γδ T cells: many paths ahead of us

“… 210 A large number of substances have been shown to epigenetically modify gene expression at the level of DNA methylation and histone modification, and several drugs, including the histone deacetylase inhibitor valproic acid (VPA) and the DNA demethylating agent decitabine, are clinically used. 212 VPA was shown to synergize with ZOL in enhancing γδ T cell cytotoxicity at the level of pAg production 213 but also affected the interaction between γδ T cells and tumor cells at the level of the NKG2D receptor/ligand axis. 214 By contrast, decitabine increased the sensitivity of osteosarcoma cells to Vδ2 T cell killing by upregulating the cell surface expression of NKG2D ligands.…”

Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells

“…In the present experimental model, γδ T cells exhibited degranulation in response to Panc89 (pancreatic adenocarcinoma cells), but not to PC-3 (prostate carcinoma cells), which corroborates the functional role of γδ T EM subset. In the case of oral-, colon-carcinoma cells and B lymphoblastic cell line (47) and osteosarcoma (48), γδ T cells exerted this cytotoxicity mainly via TCRγδ- and Fas-/perforin-mediated mechanisms, or by blocking PD-1 signal after VPA and Zol treatment (with a minor role of NKG2D and TRAIL), respectively. In the future, we will analyze the expression of perforin and granzymes, PD-1 and NKG2D to explore the mediators of cytotoxicity, exerted by T EM γδ T cells under such in vitro conditions mimicking the tumor microenvironment.…”

A Review of T-Cell Related Therapy for Osteosarcoma

“…Muraro et al reported the suppressive ability of γδ T-cells in osteosarcoma cell lines using zoledronate as a stimulus [ 67 ]. Recent studies focused on combination strategies with zoledronate and decitabine [ 68 ] or valproic acid [ 69 ].…”