B7 homolog 6 (B7H6), also known as NCR3LG1 (natural killer cell cytotoxicity receptor 3 ligand 1), is a human-specific B7 family member that binds to and activates the NKp30 receptor. B7H6 is typically not expressed on normal human tissues, but it is expressed on approximately 20% of human tumor cell lines including melanoma, carcinomas, T and B lymphomas, and myeloid leukemias, as well as primary tumor blood and bone marrow cells [3, 4]. Besides its expression in cancer, B7H6 is upregulated under inflammatory conditions such as atopic dermatitis [5], and it is induced upon stimulation by ligands of toll-like receptors or proinflammatory cytokines at the surface of proinflammatory monocytes and neutrophils [6]. B7H6 is also important for fighting viral infections. Some viruses, such as the human cytomegalovirus (HCMV) and the human herpesvirus 6, evolve mechanisms to downregulate B7H6, a strategy that probably helps to escape immune detection [7,8,9]. Other viruses not equipped with these machineries, such as the human immunodeficiency virus 2 (HIV-2), confer the upregulation of B7H6 [10]. The wide expression profile on tumors and the lack of expression on healthy tissues highlight B7H6 as a promising target for immunotherapies. B7H6-specific chimeric antigen receptor (CAR) T cells and B7H6-specific bispecific T cell engagers (BiTEs) show a potent antitumor activity in vitro and in vivo [11, 12]. While being a potential target for cancer immunotherapy, the mechanisms that control B7H6 expression in tumors are poorly understood. It was recently reported that B7H6 transcription is regulated via the proto-oncogene Myc in a variety of tumor cells [13] and by the long non-coding RNA LINC00673 in breast cancer [14]. However, these mechanisms cannot account for the entire expression pattern of B7H6 in tumors.