Credit: GETTY

Tumorigenesis can often be initiated by abnormal cell division or fusion leading to tetraploid cells that have four complete sets of chromosomes rather than the usual two. Tetraploid cells are genomically unstable, which can stimulate cell-intrinsic tumour-suppressive mechanisms involving the DNA damage response and apoptotic cell death. A new study in Science now reports that polyploidy can also trigger a cell-extrinsic antitumour response involving immunosurveillance by T cells.

calreticulin exposure is a 'marker' of polyploid cells that is recognized by the immune system to control tumour development

Tumour cell death induced by cytotoxic agents can involve the immune system when the endoplasmic reticulum (ER) protein calreticulin is translocated to the cell surface as a result of ER stress. Calreticulin is an 'eat me' signal for phagocytic cells, which then present tumour antigens to cytotoxic T cells. This study shows that calreticulin exposure on many cell types can be induced by agents that induce polyploidization, and that this is accompanied by hallmarks of the ER stress response.

So, if polyploidy is associated with calreticulin exposure, are polyploid cells under immunosurveillance? When parental (diploid) or polyploid mouse colon cancer (CT26) cells were injected subcutaneously into immunocompetent (wild-type) syngeneic mice, the polyploid cells gave rise to fewer tumours, and these tumours grew at a slower rate compared with those generated by the parental cells. There was no difference in terms of tumour formation between polyploid and parental cells in immunodeficient (Rag2−/−Il2rg−/−) mice, or in wild-type mice when calreticulin expression by polyploid cells was prevented by RNA interference. Furthermore, wild-type mice that did not develop tumours after the injection of calreticulin-expressing polyploid CT26 cells gained protection against the formation of tumours by parental CT26 cells that were subsequently injected.

Together, the results indicate that calreticulin-expressing polyploid cells induce a tumour-suppressive immune response. In line with this, tumour formation by polyploid cells could be increased by the depletion of CD4+ or CD8+ T cells, or by deficiency of interferon-γ (IFNγ) or the type I IFN receptor. Also, T cells primed in vivo by polyploid tumour cells had a more efficient recall response to tumour antigens in vitro than did T cells primed with parental tumour cells, and T cell priming by polyploid tumour cells was decreased by inhibiting calreticulin expression.

Antitumour immune responses often lead to the outgrowth of less-immunogenic tumour cell variants (a process termed immunoselection). Tumours arising from polyploid CT26 clones in wild-type mice had decreased nuclear sizes and numbers of chromosomes compared with the tumours in immunodeficient mice, and these features were associated with lower levels of calreticulin exposure. Hence, immunoselection can result in decreased tumour cell ploidy, less calreticulin exposure and therefore decreased immunogenicity.

Finally, the authors analysed breast cancer tissue from 60 patients with locally advanced breast cancer. The rare residual tumour cells in patients who responded successfully to neoadjuvant chemotherapy (the efficacy of which depends partly on an immune response) had decreased nuclear sizes compared with tumour cells from non-responsive patients. Decreased nuclear size — which might indicate decreased ploidy — correlated with an increased ratio of CD8+ T cells to FOXP3+ regulatory T cells.

The results indicate that calreticulin exposure is a 'marker' of polyploid cells that is recognized by the immune system to control tumour development. Indeed, stable expression of a membrane-bound form of calreticulin limited the aggressiveness of CT26 cells in the absence of polyploidy.