Gonzalez, Veronica DHuang, Ying-WenDelgado-Gonzalez, AntonioChen, Shih-YuDonoso, KenyiSachs, KarenGentles, Andrew JAllard, Grace MKolahi, Kevin SHowitt, Brooke EPorpiglia, ErmelindaFantl, Wendy J2025-01-072025-01-072021https://hdl.handle.net/10668/27816Tubo-ovarian high-grade serous carcinoma (HGSC) is unresponsive to immune checkpoint blockade despite significant frequencies of exhausted T cells. Here we apply mass cytometry and uncover decidual-like natural killer (dl-NK) cell subpopulations (CD56+CD9+CXCR3+KIR+CD3-CD16-) in newly diagnosed HGSC samples that correlate with both tumor and transitioning epithelial-mesenchymal cell abundance. We show different combinatorial expression patterns of ligands for activating and inhibitory NK receptors within three HGSC tumor compartments: epithelial (E), transitioning epithelial-mesenchymal (EV), and mesenchymal (vimentin expressing [V]), with a more inhibitory ligand phenotype in V cells. In cocultures, NK-92 natural killer cells acquire CD9 from HGSC tumor cells by trogocytosis, resulting in reduced anti-tumor cytokine production and cytotoxicity. Cytotoxicity in these cocultures is restored with a CD9-blocking antibody or CD9 CRISPR knockout, thereby identifying mechanisms of immune suppression in HGSC. CD9 is widely expressed in HGSC tumors and so represents an important new therapeutic target with immediate relevance for NK immunotherapy.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/CD9HGSCNK cellsNK immunotherapyT cellscytokine productioncytotoxicitydecidual-likeepithelial tumorepithelial-mesenchymalhigh-grade serous carcinomaimmune infiltrateimmune tolerancetrogocytosistubo-ovarian tumorAntineoplastic AgentsCarboplatinCell Line, TumorCoculture TechniquesCytokinesCytotoxicity, ImmunologicFemaleHumansImmune ToleranceKiller Cells, NaturalLymphocytes, Tumor-InfiltratingNeoplasms, Cystic, Mucinous, and SerousOvarian NeoplasmsPhenotypeReceptors, Natural Killer CellTetraspanin 29TrogocytosisTumor EscapeTumor Microenvironmentresearch article34469729open access10.1016/j.celrep.2021.1096322211-1247PMC8546503http://www.cell.com/article/S2211124721010755/pdfhttps://pmc.ncbi.nlm.nih.gov/articles/PMC8546503/pdf