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

Abstract

The immune system plays a major role in the protection against cancer. Identifying and characterizing the pathways mediating this immune surveillance are 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, using an in vitro NK cell killing system, we show that non‐cell‐autonomous mechanisms in aneuploid cells predominantly mediate their clearance by NK cells. Our data indicate that in untransformed aneuploid cells, NF‐κB signaling upregulation is central to elicit this immune response. Inactivating NF‐κB abolishes NK cell‐mediated clearance of untransformed aneuploid cells. In cancer cell lines, NF‐κB upregulation also correlates with the degree of aneuploidy. However, such upregulation in cancer cells is not sufficient to trigger NK cell‐mediated clearance, suggesting that additional mechanisms might be at play during cancer evolution to counteract NF‐κB‐mediated immunogenicity.

The impact of monosomies, trisomies and segmental aneuploidies on chromosomal stability

“…The upregulation of specific cytokines was confirmed by qRT-PCR in our trisomic clones (S5A Fig) . Rather than a cause for CIN, the pronounced upregulation of inflammatory responses could be a consequence of the elevated levels of CIN. It is known that CIN can induce such a response via the cGAS-STING pathway, as a result of micronuclei rupture or chromatin bridges [56,57] or via cGAS-independent activation of NF-kB [58]. Indeed, and in line with our missegregation data, we observed an increase in micronuclei in clones harboring trisomies but not in our monosomic clones (Fig 3D).…”

Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer

“…He et al, 2018; Sheltzer et al, 2016; Torres et al, 2007). NF-kB being a master transcription factor of senescence and inflammation drives immune sensing of chromosomally unstable cells through the recruitment of NK cells (Wang et al, 2021) and also mediates immune evasion by promoting migration, invasion and metastasis through non-canonical RELB signaling (Bakhoum & Cantley, 2018). Furthermore, NF-kB regulates PD-L1 expression through the release of inflammatory cytokines like TNFα by TAMs or IFNγ by infiltrating T and NK cells (Antonangeli et al, 2020; Budczies et al, 2017).…”

“…NK cells play a prominent role in the detection of cells with aberrant chromosome numbers and have been shown to eliminate them in vitro (Santaguida et al, 2017; Wang et al, 2021). To functionally validate the role of NK cells in immune sensing of aneuploid tumor cells in vivo , we treated Her2 and Her2-Plk1 animals with an NK blocking antibody until the appearance of a palpable tumor.…”

The Dynamic Instability of the Aneuploid Genome

“…It would be particularly interesting to assess the levels of genome instability in this cycling sub-population of cells and investigate by which mechanisms they can cope with it and remain capable to proliferate. Current available methodologies do not allow for the recovery of a population of cycling aneuploid cells suitable for further analyses (since those methodologies employ spindle poisons to separate the cycling counterparts ( Santaguida et al, 2017 ; Wang et al, 2018 ; Wang et al, 2021 )). Therefore, in the future it would be very important to develop new strategies to separate arrested and cycling aneuploid cells.…”