NKp44 recognition of platelet-derived growth factor D enhances the cytolytic activity of natural killer cells

Abstract

Abstract Natural killer (NK) cells are cytotoxic innate lymphoid cells that play a critical role in tumor surveillance by releasing proinflammatory cytokines and cytotoxic granules. NKp44 is an activating receptor that promotes NK cell secretion of TNF and IFN-γ upon engaging platelet-derived growth factor D (PDGF-DD), a ligand frequently overexpressed in aggressive malignancies, such as glioblastoma (GBM). However, whether NKp44-mediated recognition of PDGF-DD can directly enhance NK cell cytotoxicity against tumor cells remains unclear. Here we investigated the effect of PDGF-DD stimulation on NK cell cytotoxicity by analyzing the activity of cytotoxic transcriptional programs and cytolytic function of human NK cells in flow cytometry–based cytotoxicity assays. We demonstrate that PDGF-DD stimulation of NKp44 activates a procytotoxic transcriptional program and secretion of key cytotoxic effectors, including granzyme B, perforin, and Fas ligand. This response significantly enhanced NK cell–mediated cytotoxicity of GBM cell lines (T98G, U87, LN229 and A172) and HEK 293T cells, but not the NK-sensitive K562 cell line. Furthermore, the negation of PDGF-DD–mediated cytotoxicity and lytic granule secretion upon blockade and genetic ablation of NKp44 reveal that PDGF-DD augmentation of NK cell tumoricidal activity is tumor-type specific and reliant upon NKp44. Our data highlight a novel mechanism by which NK cells can detect soluble components of the tumor secretome, expanding the paradigm of NK cell activation beyond classical cell-surface interactions.