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High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment.
- Source :
-
Cell reports [Cell Rep] 2021 Aug 31; Vol. 36 (9), pp. 109632. - Publication Year :
- 2021
-
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.<br />Competing Interests: Declaration of interests The authors declare no competing interests. We have a published patent related to this study: WO2021/050200, PCT/US2020/046195.<br /> (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Antineoplastic Agents pharmacology
Carboplatin pharmacology
Cell Line, Tumor
Coculture Techniques
Cytokines metabolism
Cytotoxicity, Immunologic
Female
Humans
Killer Cells, Natural drug effects
Killer Cells, Natural metabolism
Lymphocytes, Tumor-Infiltrating drug effects
Lymphocytes, Tumor-Infiltrating metabolism
Neoplasms, Cystic, Mucinous, and Serous drug therapy
Neoplasms, Cystic, Mucinous, and Serous metabolism
Neoplasms, Cystic, Mucinous, and Serous pathology
Ovarian Neoplasms drug therapy
Ovarian Neoplasms metabolism
Ovarian Neoplasms pathology
Phenotype
Receptors, Natural Killer Cell metabolism
Tetraspanin 29 metabolism
Trogocytosis
Immune Tolerance drug effects
Killer Cells, Natural immunology
Lymphocytes, Tumor-Infiltrating immunology
Neoplasms, Cystic, Mucinous, and Serous immunology
Ovarian Neoplasms immunology
Tumor Escape drug effects
Tumor Microenvironment immunology
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 36
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 34469729
- Full Text :
- https://doi.org/10.1016/j.celrep.2021.109632