Dendritic cells cross-talk with tumour antigen-specific CD8+ T cells, Vγ9γδT cells and Vα24NKT cells in patients with glioblastoma multiforme and in healthy donors.

Abstract

SummaryThe finding that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs for developing more effective vaccines for DC therapy. The expression of cytomegalovirus (CMV) antigens in glioblastoma multiforme (GBM) presents a unique opportunity to target these viral proteins for tumour immunotherapy. Here, we demonstrate that Vγ9γδT cells, innate immune cells activated by zoledronate (Z) and Vα24 natural killer (Vα24NK) cells, innate/adaptive immune cells activated by α‐galactosylceramide (G) can link innate and adaptive immunities through cross‐talk with interferon (IFN) DCs from patients with glioblastoma multiforme (GBM) and healthy donors in a manner that can amplify the activation and proliferation of CMVpp65‐specific CD8+ T cells. The IFN DCs derived from patients with GBM used in this study express lower levels of programmed cell death ligand (PD)‐L1 and PD‐L2 and higher levels of C‐C receptor 7 (CCR7) than the most commonly used mature interleukin (IL)‐4 DCs. The expression level of programmed cell death 1 (PD‐1) on CD8+ T cells, including CMVpp65‐specific CD8+ T cells, expanded by IFN DCs pulsed with the CMVpp65‐peptide and Z plus G (IFN DCs/P+Z+G), was lower than that expanded by IFN DCs pulsed with the peptide alone (IFN DCs/P). Multi‐functional T cells, including human leucocyte antigen (HLA)‐A*0201‐restricted CMVpp65‐specific CD8+ T cells, Vγ9γδT cells and Vα24NKT cells, efficiently kill the HLA‐A*0201‐positive GBM cell line expressing CMVpp65 protein (T98G). These findings indicate that DC therapy using IFN DCs/P+Z+G and/or CTL therapy using CMVpp65‐specific CD8+ T cells expanded by IFN DCs/P+Z+G may lead to a good clinical outcome for patients with GBM.