Mad2 Induced Aneuploidy Contributes to Eml4-Alk Driven Lung Cancer by Generating an Immunosuppressive Environment

Abstract

Simple SummaryIn tissue homeostasis, aneuploid cells have been suggested to be recognized and eliminated by immune cells. However, these initiating cancer cells can evade the immune system and ultimately derivate a tumor. To better understand how aneuploidy might contribute to tumor initiation and/or progression, we used two lung cancer models: one in which cancer cells are aneuploid and the surrounding normal epithelial cells are diploid, and a second one in which both tumor and normal cells are aneuploid. We show that aneuploid cells surrounding the tumor generate an immunosuppressive environment that contributes to lung cancer initiation.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 Mad2 was almost entirely restricted to normal epithelial cells of the lung, and combined it with an oncogenic Eml4-Alk chromosome inversion. This combination resulted in a higher tumor burden and an increased number of tumor nodules compared to control Eml4-Alk mice alone. The FISH analysis detected significant differences in the aneuploidy levels in the non-tumor regions of Eml4-Alk+Mad2 compared to Eml4-Alk 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.