J Immunol. 2026 Jul 10;215(7):vkag204. doi: 10.1093/jimmun/vkag204.
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.
PMID:42522261 | DOI:10.1093/jimmun/vkag204