Cancer cells educate natural killer cells to a metastasis-promoting cell state

Natural killer (NK) cells have potent antitumor and antimetastatic activity. It is incompletely understood how cancer cells escape NK cell surveillance. Using ex vivo and in vivo models of metastasis, we establish that keratin-14+ breast cancer cells are vulnerable to NK cells. We then discovered th...

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Vydáno v:The Journal of cell biology Ročník 219; číslo 9
Hlavní autoři: Chan, Isaac S, Knútsdóttir, Hildur, Ramakrishnan, Gayathri, Padmanaban, Veena, Warrier, Manisha, Ramirez, Juan Carlos, Dunworth, Matthew, Zhang, Hao, Jaffee, Elizabeth M, Bader, Joel S, Ewald, Andrew Josef
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 07.09.2020
Témata:
Animals
Breast Neoplasms - immunology
Cell Line, Tumor
Female
Humans
Killer Cells, Natural - immunology
MCF-7 Cells
Methyltransferases - immunology
Mice
Neoplasm Metastasis - immunology
Receptors, Immunologic - immunology
ISSN:1540-8140, 1540-8140
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Shrnutí:Natural killer (NK) cells have potent antitumor and antimetastatic activity. It is incompletely understood how cancer cells escape NK cell surveillance. Using ex vivo and in vivo models of metastasis, we establish that keratin-14+ breast cancer cells are vulnerable to NK cells. We then discovered that exposure to cancer cells causes NK cells to lose their cytotoxic ability and promote metastatic outgrowth. Gene expression comparisons revealed that healthy NK cells have an active NK cell molecular phenotype, whereas tumor-exposed (teNK) cells resemble resting NK cells. Receptor-ligand analysis between teNK cells and tumor cells revealed multiple potential targets. We next showed that treatment with antibodies targeting TIGIT, antibodies targeting KLRG1, or small-molecule inhibitors of DNA methyltransferases (DMNT) each reduced colony formation. Combinations of DNMT inhibitors with anti-TIGIT or anti-KLRG1 antibodies further reduced metastatic potential. We propose that NK-directed therapies targeting these pathways would be effective in the adjuvant setting to prevent metastatic recurrence.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1540-8140
1540-8140
DOI:10.1083/jcb.202001134