AUTHOR=Bhat Jaydeep , Dubin Samuel , Dananberg Alexandra , Quabius Elgar Susanne , Fritsch Juergen , Dowds C. Marie , Saxena Ankit , Chitadze Guranda , Lettau Marcus , Kabelitz Dieter 

TITLE=Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00569

DOI=10.3389/fimmu.2019.00569

ISSN=1664-3224

ABSTRACT=<p>The functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ 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 <italic>in vitro</italic> tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in γδ T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in γδ T cells, we showed constitutive H3K9ac<sup>low</sup> and inducible H3K9ac<sup>high</sup> expression in Vδ2 T cells. The detailed analysis of H3K9ac<sup>low</sup> Vδ2 T cells revealed a significant reversion of T<sub>EMRA</sub> to T<sub>EM</sub> phenotype during <italic>in vitro</italic> co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate γδ T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the γδ T-cell-based immunotherapy for the treatment of certain types of cancer.</p>