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

Abstract

SUMMARYSomatic chromosomal deletions are prevalent in cancer, yet their functional contributions remain ill-defined. Among the most prominent of these events are deletions of chromosome 9p21.3, which disable a cell intrinsic barrier to tumorigenesis by eliminating the CDKN2A/B tumor suppressor genes. However, half of 9p21.3 deletions encompass a cluster of 16 type I interferons (IFNs) whose co-deletions have not been functionally characterized. To dissect how 9p21.3 and other genomic deletions impact cancer, we developed MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements), a genome engineering strategy that enables flexible modeling of megabase-sized deletions. Generation of 9p21.3-syntenic deletions in a mouse model of pancreatic cancer revealed that concomitant loss of Cdkn2a/b and the IFN cluster led to immune evasion and metastasis compared to Cdkn2a/b-only deletions. Mechanistically, IFN co-deletion disrupted type I IFN signaling, altered antigen-presenting cells, and facilitated escape from CD8+ T cell surveillance in a cell extrinsic manner requiring loss of interferon epsilon (Ifne). Our results establish co-deletions of the IFN cluster as a pervasive route to tumor immune evasion and metastasis, revealing how deletions can disable physically linked cell intrinsic and extrinsic tumor suppression. Our study establishes a framework to dissect the functions of genomic deletions in cancer and beyond.

Somatic 9p24.1 alterations in HPV – head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity

“…This highlights the importance of determining mechanisms of 9p band somatic alteration–related immune modulation in different tumor types, especially if these genomic features are to be used as biomarker tests to guide precision ICT. In PAAD, for example, we found that 9p21.3 loss was the prominent driver of low immune score/CD8 T cells, in accordance with recent evidence in pancreatic cancer mouse models ( 43 ).…”

Therapy sculpts the complex interplay between cancer and the immune system during tumour evolution

“…Loss of chromosome arm 9p or parts thereof has been proposed to be used as an alternative to TMB or PD-L1 staining for ICB efficacy predictions [31,32]. This is likely due to deletions encompassing the Interferon gene cluster, which are often found to be co-deleting the tumour suppressor locus CDKN2A, rendering cells less immunocompetent and more proliferative [33].…”