Chromosome 9p21.3 Coordinates Cell Intrinsic and Extrinsic Tumor Suppression

ABSTRACT: Somatic chromosomal deletions are prevalent in cancer, yet their effects are poorly understood. The most prominent homozygous deletions affect chromosome 9p21.3 and eliminate the CDKN2A/B tumor suppressor genes, thus disabling a cell intrinsic barrier to tumorigenesis. However, half of 9p21.3 deletions encompass a cluster of 16 type I interferons (IFNs) whose co-deletion remains unexplored. To functionally dissect 9p21.3 and other genomic deletions, we developed MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements), a genome engineering strategy that enables flexible modeling of megabase-sized deletions. Applying MACHETE to a syngeneic mouse model of pancreatic cancer, we show that concomitant loss of the IFN cluster with Cdkn2a/b enhanced immune evasion, metastasis, and immunotherapy resistance compared to Cdkn2a/b deletions alone. 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 (Ifne). These results reveal how IFN-encompassing 9p21.3 deletions disable cell intrinsic and extrinsic tumor suppression, thereby providing a pervasive route for immune evasion, metastasis, and immunotherapy resistance. Our study provides a framework for interrogating large deletion events in cancer and beyond.

ORGANISM(S): Mus musculus

PROVIDER: GSE210593 | GEO | 2022/09/08

REPOSITORIES: GEO