Many tumor types exhibit chromosomal instability (CIN), characterized by a dynamic genome that exhibits large-scale changes in organization and composition. On its face, these conditions should prime the tumor cell for recognition by the immune system through diverse mechanisms such as neoantigen production and DNA damage. However, despite the theoretical immune liability posed by CIN in cancer, advanced tumors often exhibit CIN alongside evidence of immune escape, suggesting adaptive mechanisms that enable the survival and propagation of chromosomally unstable cells. The tradeoffs and interplay between CIN and immune avoidance are not well established, and a deeper understanding could provide insight into cancer evolution and CIN-specific vulnerabilities.
This ASPIRE award, shared between the McClelland, Bakhoum, and Foijer laboratories, seeks to address this paradoxical coexistence of high CIN and immune avoidance. Utilizing models of ovarian and breast cancer, this project will investigate the intricate relationship between CIN, aneuploidy, and the tumor microenvironment (TME). By employing cutting-edge single-cell genome sequencing and unique mouse models, the research aims to identify which aneuploidies the immune system recognizes and how ongoing chromosome missegregation impacts the TME. By establishing a productive collaborative network and leveraging complementary resources and expertise, the study aims to lay the foundation for a comprehensive investigation into the complex interplay between CIN and the TME. The project may enhance clinical outcomes in cancer patients by identifying immune evasion mechanisms that lay the groundwork for novel immunotherapeutic targets.