Abstract
The functional plasticity and anti-tumor potential of human gamma delta T cells have been widely studied. However, the epigenetic regulation of gamma delta T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands ...
Abstract
The functional plasticity and anti-tumor potential of human gamma delta T cells have been widely studied. However, the epigenetic regulation of gamma delta T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in gamma delta T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in gamma delta T cells, we showed constitutive H3K9ac(low) and inducible H3K9ac(high) expression in V delta 2 T cells. The detailed analysis of H3K9ac(low) V delta 2 T cells revealed a significant reversion of T-EMRA to T-EM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate gamma delta T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the gamma delta T-cell-based immunotherapy for the treatment of certain types of cancer.
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