Abstract
BackgroundAdoptive immunotherapy is gaining momentum to fight malignancies, whereby γδ T cells have received recent attention as an alternative cell source as to natural killer cells and αβ T cells. The advent of γδ T cells is largely due to their ability to recognize and target tumor cells using both innate characteristic and T cell receptor (TCR)-mediated mechanisms, their capacity to enhance the generation of antigen-specific T cell responses, and their potential to be used in an autologous or allogeneic setting.MethodsIn this study, we explored the beneficial effect of the immunostimulatory cytokine interleukin (IL)-15 on purified γδ T cells and its use as a stimulatory signal in the ex vivo expansion of γδ T cells for adoptive transfer. The expansion protocol was validated both with immune cells of healthy individuals and acute myeloid leukemia patients.ResultsWe report that the addition of IL-15 to γδ T cell cultures results in a more activated phenotype, a higher proliferative capacity, a more pronounced T helper 1 polarization, and an increased cytotoxic capacity of γδ T cells. Moreover γδ T cell expansion starting with peripheral blood mononuclear cells from healthy individuals and acute myeloid leukemia patients is boosted in the presence of IL-15, whereby the antitumor properties of the γδ T cells are strengthened as well.ConclusionsOur results support the rationale to explore the use of IL-15 in clinical adoptive therapy protocols exploiting γδ T cells.
Highlights
Adoptive immunotherapy is gaining momentum to fight malignancies, whereby γδ T cells have received recent attention as an alternative cell source as to natural killer cells and αβ T cells
Stimulatory effects were seen to some extent with the combination of IL-2+Isopentenyl pyrophosphate (IPP), as evidenced by carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution, no statistical significance was reached relative to unstimulated γδ T cells
Calculating mean fold expansion, being the number of γδ T cells after stimulation divided by the number of γδ T cells at the start, IL-2+IPP and IL-15 +IPP stimulation resulted in a mean fold expansion of 1.35 ± 0.15 x106 and 2.18 ± 0.31 x106 γδ T cells, respectively
Summary
Adoptive immunotherapy is gaining momentum to fight malignancies, whereby γδ T cells have received recent attention as an alternative cell source as to natural killer cells and αβ T cells. In pursuit of new treatment options, several lines of evidence suggest that immunotherapy is an active modality in AML [11] This includes the graft-versusleukemia effect associated with allogeneic hematopoietic stem cell transplantation (HSCT), where it has been demonstrated that elevated γδ T cell immune recovery after HSCT is associated with a better outcome in terms of infections, graft-versus-host disease and overall survival [12,13,14]. Adoptive transfer of γδ T cells is an interesting alternative to tackle minimal residual disease and the high relapse rate in AML patients, optionally in combination with HSCT [17] or other (new) therapeutic agents [18,19,20]. While γδ T cell therapy holds great promise, clinical results are far modest, underscoring the need to further enhance the immunogenicity of the γδ T cell product [21]
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