Aneuploid cells activate NF-κB to promote their immune clearance by NK cells

The immune system plays a major role in the protection against cancer. Identifying and characterizing the pathways mediating this immune surveillance is thus critical for understanding how cancer cells are recognized and eliminated. Aneuploidy is a hallmark of cancer and we previously found that untransformed cells that had undergone senescence due to highly abnormal karyotypes are eliminated by Natural Killer (NK) cells in vitro. However, the mechanisms underlying this process remained elusive. Here we show that NK-mediated immune clearance of aneuploid cells is predominantly mediated by non-cell autonomous mechanisms. Our data indicate that NF-κB signaling in aneuploid cells is central to elicit this immune response. Inactivating NF-κB abolishes NK-cell mediated clearance of untransformed aneuploid cells in vitro. In cancer cell lines, NF-κB activation correlates with degree of aneuploidy, raising the possibility that aneuploidy-induced immune recognition is partially retained in cancer. In one experiment, six replicates of untreated RPE-1 hTERT cells were compared to three replicates of doxorubicin treated, palbociclib treated, nutlin3 treated, aneuploid cycling, or ArCK cells generated in the same cell line background. In the second experiment, two replicates of euploid cycling cells were compared to two replicates of ArCK cells generated in the control background. Three replicates of euploid cycling cells were compared to three replicates of ArCK cells generated in the STAT1 KO background.