High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment.
Cell Rep
; 36(9): 109632, 2021 08 31.
Article
em En
| MEDLINE
| ID: mdl-34469729
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Células Matadoras Naturais
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Linfócitos do Interstício Tumoral
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Neoplasias Císticas, Mucinosas e Serosas
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Evasão Tumoral
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Microambiente Tumoral
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Tolerância Imunológica
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article