RT Journal Article
T1 High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment.
A1 Gonzalez, Veronica D
A1 Huang, Ying-Wen
A1 Delgado-Gonzalez, Antonio
A1 Chen, Shih-Yu
A1 Donoso, Kenyi
A1 Sachs, Karen
A1 Gentles, Andrew J
A1 Allard, Grace M
A1 Kolahi, Kevin S
A1 Howitt, Brooke E
A1 Porpiglia, Ermelinda
A1 Fantl, Wendy J
K1 CD9
K1 HGSC
K1 NK cells
K1 NK immunotherapy
K1 T cells
K1 cytokine production
K1 cytotoxicity
K1 decidual-like
K1 epithelial tumor
K1 epithelial-mesenchymal
K1 high-grade serous carcinoma
K1 immune infiltrate
K1 immune tolerance
K1 trogocytosis
K1 tubo-ovarian tumor
AB Tubo-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.
YR 2021
FD 2021
LK https://hdl.handle.net/10668/27816
UL https://hdl.handle.net/10668/27816
LA en
DS RISalud
RD Apr 8, 2025