Mad2 Induced Aneuploidy Contributes to Driven Lung Cancer by Generating an Immunosuppressive Environment.

Aneuploidy, an imbalance number of chromosomes, is frequently observed in lung cancer and inversely correlates with patient survival. Paradoxically, an aneuploid karyotype has detrimental consequences on cellular fitness, and it has been proposed that aneuploid cells, at least in vitro, generate signals for their own elimination by NK cells. However, how aneuploidy affects tumor progression as well as the interplay between aneuploid tumor cells and the tumor microenvironment is still unclear. We generated a new mouse model in which overexpression of was almost entirely restricted to normal epithelial cells of the lung, and combined it with an oncogenic chromosome inversion. This combination resulted in a higher tumor burden and an increased number of tumor nodules compared to control mice alone. The FISH analysis detected significant differences in the aneuploidy levels in the non-tumor regions of + compared to alone, although both tumor groups presented similar levels of aneuploidy. We further show that aneuploid cells in the non-tumor areas adjacent to lung tumors recruit immune cells, such as tumor-associated macrophages. In fact, these areas presented an increase in alveolar macrophages, neutrophils, decreased cytotoxic CD8 T cells, and IFN-γ, suggesting that aneuploid cells in the surrounding tumor areas create an immunosuppressive signature that might contribute to lung tumor initiation and progression.