MACHETE identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis

• DOI: 10.1038/s43018-022-00443-5
• Publication Date: 2022-11-07T17:03:57Z
• Authors: Francisco M. Barriga; Kaloyan M. Tsanov; Yu-Jui Ho; Noor Sohail; Amy Zhang; Timour Baslan; Alexandra N. Wuest; Isabella Del Priore; Brigita Meškauskaitė; Geulah Livshits; Direna Alonso-Cur...; Janelle Simon; Almudena Chaves-P...; Dafna Bar-Sagi; Christine A. Iaco...; Faiyaz Notta; Ronan Chaligne; Roshan Sharma; Dana Pe’er; Scott W. Lowe
• Keywords: 0301 basic medicine; chromosomes; tumor suppressor; genes: types; neoplasms; mammal; Article; Chromosomes; Mice; 03 medical and health sciences; Neoplasms; Tumor Microenvironment; cancer; Animals; genetics & nucleic acid processing; animal; chromosome; RNA structure; genes; mouse; Immune Evasion; genomics and proteomics; function; modification; rodent; bioinformatics; DNA; 3. Good health; diseases & disorders; Tandem Repeat Sequences; structure and function; Interferons; Chromosome Deletion

AbstractThe 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.