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

Abstract

SummaryThe 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. We previously found that untransformed cells that had undergone senescence due to highly abnormal karyotypes are eliminated by Natural Killer (NK) cells in vitro. Here we show that this is also true for aneuploid untransformed cells that had not lost their ability to proliferate. Their elimination by NK cells, like that of aneuploid senescent cells, is predominantly mediated by non-cell autonomous mechanisms. Our data further indicate that NF-κB signaling in aneuploid cells is central to eliciting this immune response. Inactivating NF-κB abolishes NK-cell mediated clearance in aneuploid cells in vitro. In cancer cell lines, NF-κB signaling correlates with degree of aneuploidy, raising the possibility that aneuploidy-induced immune recognition is partially retained in cancer.

Karyotype Aberrations in Action: The Evolution of Cancer Genomes and the Tumor Microenvironment

“…CIN may also help cells overcome immunodetection, although in many cases the exact mechanism is not clear. One study found CIN initially increased tumor cell immunogenicity, consistent with other reports [322,326], but continued evolution under immune selection promotes the proliferation of aneuploid cells that are able to suppress MHC class I antigen presentation and avoid immune detection [329]. A possible mechanism by which CIN and karyotype changes can mediate immune evasion is arm-level or focal deletions on chromosome 6 that result in human leukocyte antigen LOH, which was detected in about 40% of non-small cell lung cancers [330].…”

“…The mechanisms relating aneuploidy and immune interactions within tumors are not well understood, as highlighted by recent contrasting observations. One study found that aneuploid cells activated NF-κB signaling to promote their clearance by immune cells, and the NF-κB activity correlated with the degree of aneuploidy in cancer cell lines [ 326 ]. In clinical samples, however, highly aneuploid tumors had lower levels of NF-κB activity [ 35 ].…”

“…Immune pressure can dramatically influence clonal selection in tumors [ 332 ], leading to the dominance of less immunogenic sub-clones with favorable genomic and epigenetic alterations. Based on the apparent immunogenicity of aneuploid cells [ 322 , 323 , 326 , 329 ], it is tempting to speculate that the physiological consequences of aneuploidy, such as inflammation and the recruitment of immune cells, create a hostile immune predatory environment at first, but through ongoing genomic and environmental evolution a beneficial, immune suppressive TME and/or less immunogenic sub-clones emerge ( Figure 3 ). Further work is needed to elucidate these dynamics through rigorous experimental studies.…”

Small but strong: Mutational and functional landscapes of micronuclei in cancer genomes

“…Interestingly, recent evidence has suggested that some of the cycling micronucleated aneuploid RPE-1 cells can be cleared by natural killer cells. 98 This opens up the intriguing and yet unexplored possibility that the long-term consequences of micronucleus may also depend on whether the micronucleated cells would be recognized and eliminated by immune system.…”

“…Overall, we anticipate the long‐term mutational and functional consequences of micronucleus depends on complex cellular contexts, including the status and levels of p53, extent of genomic imbalances in main nucleus, 96 the manner in which micronucleus is generated, identity of micronucleated chromosomes or mutation types generated in micronucleus. Interestingly, recent evidence has suggested that some of the cycling micronucleated aneuploid RPE‐1 cells can be cleared by natural killer cells 98 . This opens up the intriguing and yet unexplored possibility that the long‐term consequences of micronucleus may also depend on whether the micronucleated cells would be recognized and eliminated by immune system.…”