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

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

Authors:	Barriga, F. M.; Tsanov, K. M.; Ho, Y. J.; Sohail, N.; Zhang, A.; Baslan, T.; Wuest, A. N.; Del Priore, I.; Meškauskaitė, B.; Livshits, G.; Alonso-Curbelo, D.; Simon, J.; Chaves-Perez, A.; Bar-Sagi, D.; Iacobuzio-Donahue, C. A.; Notta, F.; Chaligne, R.; Sharma, R.; Pe’er, D.; Lowe, S. W.
Article Title:	MACHETE identifies interferon-encompassing chromosome 9p21.3 deletions as mediators of immune evasion and metastasis
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. © 2022, The Author(s).
Keywords:	genetics; interferon; neoplasm; neoplasms; chromosome; mouse; animal; animals; mice; chromosome deletion; chromosomes; tumor microenvironment; immune evasion; interferons; butachlor
Journal Title:	Nature Cancer
Volume:	3
Issue:	11
ISSN:	2662-1347
Publisher:	Nature Research
Date Published:	2022-11-01
Start Page:	1367
End Page:	1385
Language:	English
DOI:	10.1038/s43018-022-00443-5
PUBMED:	36344707
PROVIDER:	scopus
PMCID:	PMC9701143
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85141420027&doi=10.1038%2fs43018-022-00443-5&partnerID=40&md5=36aa849d962c42a43b5dfd6a4aa6e423
Notes:	Article -- Export Date: 3 January 2023 -- Source: Scopus