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

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Homozygous deletions at chromosome 9p21.3 are common in cancer, affecting CDKN2A/B tumor suppressors.
• These deletions can also encompass a type I interferon (IFN) gene cluster, with unexplored consequences.

Purpose of the Study:

• To functionally dissect the impact of large genomic deletions, including 9p21.3, on cancer progression.
• To investigate the consequences of co-deleting tumor suppressors and type I IFN genes.

Main Methods:

• Development of a flexible deletion engineering strategy called MACHETE (molecular alteration of chromosomes with engineered tandem elements).
• Application of MACHETE to a syngeneic mouse model of pancreatic cancer.

Main Results:

• Co-deletion of the IFN cluster promoted immune evasion, metastasis, and immunotherapy resistance in pancreatic cancer models.
• IFN co-deletion disrupted type I IFN signaling, altering tumor microenvironment immune cells and enabling escape from CD8+ T-cell surveillance.
• Interferon epsilon was identified as a key driver of these immune-related effects.

Conclusions:

• A specific chromosomal deletion can simultaneously disable cell-intrinsic (tumor suppressors) and cell-extrinsic (immune surveillance) tumor suppression.
• This study provides a novel framework for interrogating large genomic deletions in cancer and other diseases.
• Targeting type I IFN signaling presents a potential therapeutic strategy for cancers with 9p21.3 deletions.