The p53 tumor suppressor modulates the expression of proteins that control natural killer cell activity

Natural killer (NK) cells are at the forefront of the fight against infections and cancer, where they recognize targets through a system of inhibitory and activating ligands expressed on monitored cells. The transcriptional regulation of such ligands in tumors remains poorly understood. Our previous transcriptomic studies suggest that the tumor suppressor p53 may upregulate key NK-activating ligands, including SLAM family member 7 (SLAMF7) and natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1). Herein, we aimed to validate the functional role of this regulatory axis. Isogenic p53-proficient and p53-deficient cell lines from diverse cancer types (A549, NCI-H460, U-2 OS) were used to examine p53-dependent regulation of SLAMF7 and NCR3LG1. Luciferase reporter assays assessed putative p53-responsive enhancer elements, with pharmacological activation of p53 achieved using DNA-damaging agents (actinomycin D and camptothecin) and the MDM2 proto-oncogene inhibitor nutlin-3a. The functional impact of NK cell-mediated cytotoxicity was assessed using primary human NK cells and the NK-92 cell line. Pharmacological activation of p53 using camptothecin or combined actinomycin D and nutlin-3a strongly induced SLAMF7 and NCR3LG1 expression in p53-proficient, but not p53-deficient, cancer cell lines. The SLAMF7 protein, typically expressed only in immune cells, was strongly induced in epithelial and mesenchymal cancer models following p53 activation. Paclitaxel upregulated SLAMF7 independently of p53, suggesting an alternative pathway of induction. Notably, dual treatment with actinomycin D and nutlin-3a induced the secretion of soluble SLAMF7. Also, NCR3LG1 was strongly upregulated in a p53-dependent fashion. The cloned fragments of these genes, located in regions suggestive of enhancer activity, conferred p53 responsiveness to the reporter gene. Functionally, dual p53 activation by actinomycin D and nutlin-3a significantly increased tumor cell susceptibility to cytolysis by both primary human NK cells and the NK-92 cell line. SLAMF7 expression can be induced in non-hematological cancers by p53-dependent and p53-independent mechanisms following exposure to anticancer agents. Given that SLAMF7 is a clinically validated target of the monoclonal antibody Elotuzumab in multiple myeloma, its drug-inducible expression in solid tumors is of particular interest. This finding may support the development of novel therapeutic strategies incorporating SLAMF7-targeting antibodies in p53-competent non-hematologic malignancies.