Barriga, Francisco M, Tsanov, Kaloyan M, Ho, Yu-Jui, Sohail, Noor, Zhang, Amy, Baslan, Timour, Wuest, Alexandra N, Del Priore, Isabella, Meškauskaitė, Brigita, Livshits, Geulah, Alonso-Curbelo, Direna, Simon, Janelle, Chaves-Perez, Almudena, Bar-Sagi, Dafna, Iacobuzio-Donahue, Christine A, Notta, Faiyaz, Chaligne, Ronan, Sharma, Roshan, Pe'er, Dana, Lowe, Scott W (November 2022) MACHETE identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis. Nature Cancer, 3 (11). pp. 1367-1385. ISSN 2662-1347
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MACHETE identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis.pdf - Published Version Available under License Creative Commons Attribution. Download (21MB) | Preview |
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.
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