During the first funding period, we demonstrated that Vitamin C (VitC) increases significantly the activation and effector functions of human gamma/delta T cells. VitC increases the proliferative activity, the metabolic activity, and the cytokine production in gamma/delta T cells. However, we also showed that VitC, in the additional presence of transforming growth factor-beta (TGF-beta), upregulates the expression of the transcription factor FOXP3 and induces suppressive activity in human gamma/delta T cells, associated with strong hypomethylation in specific regions of the FOXP3gene.
Transcriptome analysis performed by RNAseq and genome-wide methylation studies identified several candidates of VitC-regulated genes in human gamma/delta T cells. We also contributed to a clinical phase I study where allogeneic gamma/delta T cells expanded in presence of VitC were adoptively transferred into cancer patients.
Based on these results, the goals of the second funding period are to investigate further the influence of VitC on the plasticity of human gamma/delta T cells. We will focus on the following questions: (1) How does VitC modulate T-cell receptor signaling in gamma/delta T cells and what is the significance of some of the VitC-regulated genes identified in our previous studies; (2) How does VitC increase the cytotoxic effector function of gamma/delta T cells? (3) How does VitC in combination with other, clinically relevant epigenetic modifiers such as histone deacetylase inhibitors modulate the activation and effector functions of human gamma/delta T cells? The overall goal of this project is to optimize the effector function of human gamma/delta T cells for application in cellular immunotherapy.