All-trans Retinoic Acid (atRA) promotes tumor resistence to NK cells by downregulating tumor B7-H6 expression

Abstract

Abstract The interaction between the activating receptor NKp30 and its major tumor ligand B7-H6 is important for NK cell mediated tumor rejection while the regulation of B7-H6 by tumor therapeutics remains largely unknown. In this study, we investigated the regulation of B7-H6 by all-trans Retinoic acid (atRA), which is a terminal differentiation inducer of tumor cells and in use for tumor therapy. We found that B7-H6 expression on tumor cell suface was downregulated upon atRA treatment. We further found that atRA downregulated B7-H6 at the mRNA level. Epgenetic modifications such as DNA methylation and HDAC was not responsible as inhibitors of these pathways did not restore the B7-H6 mRNA expression. Instead, atRA downregulated c-myc and inhibited the transcription of B7-H6. NK92 and NKG cells mediated U937 cell killing was mainly dependent on the NKp30-B7-H6 interaction. Thus atRA treatment dampened U937 lysis by NK92 and NKG cells. Together, our data showed that atRA treatment downregulated B7-H6 expression and promoted tumor cell resistence to NK cells.