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

2020/07/09 by Isaac S. Chan, Hildur Knútsdóttir, Gayathri Ramakrishnan +10 · 158 citations
Immunology and Microbiology · Medicine · #Antibody #Biology #CAR-T cell therapy research #Cancer #Cancer cell #Cancer research #Cytotoxic T cell #Immune Cell Function and Interaction #Immune system #Immunology #Immunotherapy #In vitro #Interleukin 12 #Interleukin 21 #Lymphokine-activated killer cell #Metastasis #NK-92 #T-cell and B-cell Immunology #TIGIT

paper · open access · doi:10.1083/jcb.202001134

published in The Journal of Cell Biology 219(9) (Rockefeller University Press)

openalex publication_date 2020/07/09 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01

Abstract

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.

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