MACHETE identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis
Francisco M. Barriga, Kaloyan M. Tsanov, Yu-Jui Ho, Noor Sohail, Amy Zhang, Timour Baslan, Alexandra Wuest, Isabella Del Priore, Brigita Meškauskaitė, Geulah Livshits, Direna Alonso‐Curbelo, Janelle Simon, Almudena Chaves Perez, Dafna Bar‐Sagi, Christine A. Iacobuzio–Donahue, Faiyaz Notta, Ronan Chaligné, Roshan Sharma, Dana Pe’er, Scott W. Lowe
Abstract
Abstract The most prominent homozygous deletions in cancer affect chromosome 9p21.3 and eliminate CDKN2A/B tumor suppressors, disabling a cell-intrinsic barrier to tumorigenesis. Half of 9p21.3 deletions, however, also encompass a type I interferon (IFN) gene cluster; the consequences of this co-deletion remain unexplored. To functionally dissect 9p21.3 and other large genomic deletions, we developed a flexible deletion engineering strategy, MACHETE (molecular alteration of chromosomes with engineered tandem elements). Applying MACHETE to a syngeneic mouse model of pancreatic cancer, we found that co-deletion of the IFN cluster promoted immune evasion, metastasis and immunotherapy resistance. Mechanistically, IFN co-deletion disrupted type I IFN signaling in the tumor microenvironment, leading to marked changes in infiltrating immune cells and escape from CD8 + T-cell surveillance, effects largely driven by the poorly understood interferon epsilon. These results reveal a chromosomal deletion that disables both cell-intrinsic and cell-extrinsic tumor suppression and provide a framework for interrogating large deletions in cancer and beyond.