Cited by 125interferon and immune responsesCancer Immunotherapy and BiomarkersChromatin Remodeling and Cancer

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

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Barriga, Francisco M., Tsanov, Kaloyan M., Ho, Yu-Jui, Sohail, Noor, Zhang, Amy, Baslan, Timour, Wuest, Alexandra N., Del Priore, Isabella +12 more·2022·Nature Cancer

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.

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  • Interferon cluster loss creates a cold tumor immune milieu and resistance to immunotherapy.

    “Interferon cluster loss creates a “cold” tumor immune milieu and resistance to immunotherapy52”

    From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [52]

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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.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • Ontario Institute for Cancer Research (CA)
Corresponding author
Lowe, Scott W.
Venue
Nature Cancer
Published
2022-11-07
Volume
3
Issue
11
Pages
1367-1385
ISSN
2662-1347 (ISSN-L)
OpenAlex
W4308458365
Cited by
125
References
82
Citations by year
2026: 28 · 2025: 35 · 2024: 40 · 2023: 21 · 2022: 1
FWCI
9.24
Type
journal article
Language
en
Open access
Locations
  • Nature Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders
  • Howard Hughes Medical Institute (P30 CA08748)
  • Jane Coffin Childs Memorial Fund for Medical Research
  • Memorial Sloan-Kettering Cancer Center (P30-CA08748)
  • Edward P. Evans Foundation
  • Cycle for Survival
  • Marie-Josée and Henry R. Kravis Center for Molecular Oncology
  • National Cancer Institute (T32CA160001, CA08748, P01CA013106, P30CA008748)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
chromosome 9p21.3, CDKN2A/B, homozygous deletion, interferon epsilon, immune evasion, metastasis, immunotherapy resistance, tumor microenvironment, type I interferon signaling, pancreatic cancer, machete, syngeneic mouse model, tumor suppressor inactivation
MeSH terms
Animals, Chromosome Deletion, Chromosomes, Interferons, Neoplasms, Tandem Repeat Sequences, Mice, Immune Evasion, Tumor Microenvironment

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