Valproic acid enhances pamidronate-sensitized cytotoxicity of Vδ2+ T cells against EBV-related lymphoproliferative cells.

Therapeutic options for Epstein-Barr virus (EBV)-associated post-transplantation lymphoproliferative diseases (PTLD) are currently limited, accompanying with some off-target toxicities. We previously demonstrated that early recovery of Vδ2+ T cells inversely correlated to EBV reactivation after allogeneic hematopoietic cell transplantation. Studies in vitro and in the mouse models showed the cytotoxic activity of Vδ2+ T cells on EBV-transformed lymphoproliferative cells, but the efficacy was moderate. Bisphosphonate, such as pamidronate (PAM), have been reported as a sensitizer to trigger tumor cells for Vδ2+ T cells recognition. Valproic acid (VPA) has attracted attentions due to its adjuvant anti-tumor effect with chemotherapy or immunotherapy. Whether PAM and VPA facilitate the immunogenicity of EBV-infected cells towards Vδ2+ T cells cytotoxicity remains unknown. Herein, we demonstrated that lower dosage of VPA and/or PAM did not induce apoptosis of EBV-transformed B lymphoblastoid cell lines (EBV-LCLs) or Vδ2+ T cells. Notably, pre-treatment with PAM significantly increased the cell death of EBV-LCLs after co-culture with Vδ2+ T cells at different ratios. Combining treatment with VPA reinforced the sensitizing effect of PAM. This efficacy was through inducing the accumulation of mevalonate pathway intermediates and dependent on the γδ T cell receptor of Vδ2+ T cells. Similar sensitizing effects of PAM and PAM plus VPA were also demonstrated on the primary PTLD cells. These results highlight the roles of PAM and VPA in the enhancement of immune surveillance and expand the fields of these two drugs in the treatment of different types of malignancies.