TY - JOUR
T1 - Cancer cells educate natural killer cells to a metastasis-promoting cell state
AU - Chan, Isaac S.
AU - Kn utsdóttir, Hildur
AU - Ramakrishnan, Gayathri
AU - Padmanaban, Veena
AU - Warrier, Manisha
AU - Ramirez, Juan Carlos
AU - Dunworth, Matthew
AU - Zhang, Hao
AU - Jaffee, Elizabeth M.
AU - Bader, Joel S.
AU - Ewald, Andrew Josef
N1 - Publisher Copyright:
© 2020 Chan et al.
PY - 2020/9/7
Y1 - 2020/9/7
N2 - 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.
AB - 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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U2 - 10.1083/jcb.202002077
DO - 10.1083/jcb.202002077
M3 - Article
C2 - 32645139
AN - SCOPUS:85087800958
SN - 0021-9525
VL - 219
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 9
M1 - jcb.202002077
ER -