The growth of polyploid cancer cells is suppressed by T-cell–dependent immunosurveillance.

  • Major finding: The growth of polyploid cancer cells is suppressed by T-cell–dependent immunosurveillance.

  • Mechanism: Hyperploidy renders cancer cells immunogenic via ER stress and membrane calreticulin exposure.

  • Impact: Cancer cells must overcome this extrinsic immunosurveillance to survive and proliferate.

Oncogene activation stimulates growth-suppressive control mechanisms, such as the endoplasmic reticulum (ER) stress response, which triggers increased membrane exposure of calreticulin to enhance immune-mediated elimination of malignant cells. Senovilla and colleagues investigated whether polyploidization of cancer cells, a common and early event in many tumors, induces a similar immunosurveillance mechanism to constrain the growth of cells with aberrant DNA content. Treatment of mouse and human cancer cells with agents that promote hyperploidization, including cytochalasin D and nocodazole, promoted initiation of the ER stress response and relocalization of calreticulin to the cell surface, suggesting that these cells may be targeted by immunosurveillance. In support of this idea, nocodazole-treated hyperploid cells exhibited increased T-cell priming in response to tumor antigens in vitro and formed tumors less efficiently in immunocompetent mice compared with immunodeficient animals; this inhibition of tumor growth was dependent on calreticulin expression and the presence of CD4- and CD8-positive T cells and IFN activation. Tumors that did form in immunocompetent mice underwent immunoselection, resulting in decreased nuclear size and total DNA content and reduced membrane exposure of calreticulin. Interestingly, a correlation between an antitumor immune response and diminished nuclear size was observed in carcinogen- and oncogene-driven tumor models as well as in human breast cancer samples. Furthermore, ectopic expression of a membrane-targeted calreticulin protein was sufficient to limit tumor growth in immunocompetent mice in the absence of hyperploidy, indicating that surface expression of calreticulin renders cells immunogenic and triggers tumor immunosurveillance. These results identify a cell-extrinsic pathway that selects against polyploidy in tumors and suggest that malignant cells acquire mechanisms to escape this growth restraint.

Senovilla L, Vitale I, Martins I, Tailler M, Pailleret C, Michaud M, et al. An immunosurveillance mechanism controls cancer cell ploidy. Science 2012;337:1678–84.

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