The DOI matches its Crossref record; 60 of the 61 references it cites were found in a registry or an index.
Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity
Open accessAbstract
Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape 1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape 3-5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution 6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.
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“Targeting specific H3K9 methyltransferases, such as SUV39H1 and SETDB1, has been shown to enhance immunotherapy responses in various cancer models.”
From Multi-omics analysis identifies glioblastoma dependency on H3K9me3 methyltransferase activity (2025) · cites this paper as [24]
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“SETDB1 targeting can promote cytotoxic T cell-based immunotherapy in cancer mouse models24.”
From Multi-omics analysis identifies glioblastoma dependency on H3K9me3 methyltransferase activity (2025) · cites this paper as [24]
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“In contrast to other recently characterized immune evasion genes 4,8,45 , tumour-specific loss of TBK1 did not result in dramatic remodeling of the immune compartment.”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [45]
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Gene Ontology: tool for the unification of biology
Ashburner, M., Ball, C. A., Blake, J. A., Botstein, D., Butler, H., Cherry, J. M., Davis, A. P., Dolinski, K., Dwight, S. S., Eppig, J. T., et al. (2000) · Nature Genetics · doi:10.1038/75556 · Cited by 43,206
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890
An integrated encyclopedia of DNA elements in the human genome
The ENCODE Project Consortium (2012) · Nature · doi:10.1038/nature11247 · Cited by 18,072
Self-citationThe Molecular Signatures Database Hallmark Gene Set Collection
Liberzon, A., Birger, C., Thorvaldsdóttir, H., Ghandi, M., Mesirov, J. P., & Tamayo, P. (2015) · Cell Systems · doi:10.1016/j.cels.2015.12.004 · Cited by 13,807
Heinz, S., Benner, C., Spann, N., Bertolino, E., Lin, Y. C., Laslo, P., Cheng, J. X., Murre, C., Singh, H., & Glass, C. K. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.004 · Cited by 13,382
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174
Comprehensive Mapping of Long-Range Interactions Reveals Folding Principles of the Human Genome
Lieberman-Aiden, E., van Berkum, N. L., Williams, L., Imakaev, M., Ragoczy, T., Telling, A., Amit, I., Lajoie, B. R., Sabo, P. J., Dorschner, M. O., et al. (2009) · Science · doi:10.1126/science.1181369 · Cited by 8,898
Self-citationSCANPY: large-scale single-cell gene expression data analysis
Wolf, F. A., Angerer, P., & Theis, F. J. (2018) · Genome Biology · doi:10.1186/s13059-017-1382-0 · Cited by 8,881
Molecular signatures database (MSigDB) 3.0
Liberzon, A., Subramanian, A., Pinchback, R., Thorvaldsdóttir, H., Tamayo, P., & Mesirov, J. P. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr260 · Cited by 7,111
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The hallmarks of cancer immune evasion
Galassi, C., Chan, T. A.-T., Vitale, I., & Galluzzi, L. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.09.010 · Cited by 630
Padeken, J., Methot, S. P., & Gasser, S. M. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-022-00483-w · Cited by 532
Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes
Wang, T.-W., Johmura, Y., Suzuki, N., Omori, S., Migita, T., Yamaguchi, K., Hatakeyama, S., Yamazaki, S., Shimizu, E., Imoto, S., et al. (2022) · Nature · doi:10.1038/s41586-022-05388-4 · Cited by 469
Immune evasion in cancer: mechanisms and cutting-edge therapeutic approaches
Tufail, M., Jiang, C., & Li, N. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02280-1 · Cited by 454
Shi, Q., Shen, Q., Liu, Y., Shi, Y., Huang, W., Wang, X., Li, Z., Chai, Y., Wang, H., Hu, X., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.08.012 · Cited by 337
Metadata
- Authors
- Griffin, G. K., Wu, J., Iracheta-Vellve, A., Patti, J. C., Hsu, J., Davis, T., Dele-Oni, D., Du, P. P., Halawi, A. G., Ishizuka, J. J., Kim, S. Y., Klaeger, S., Knudsen, N. H., Miller, B. C., Nguyen, T. H., Olander, K. E., Papanastasiou, M., Rachimi, S., Robitschek, E. J., Schneider, E. M., Yeary, M. D., Zimmer, M. D., Jaffe, J. D., Carr, S. A., Doench, J. G., Haining, W. N., Yates, K. B., Manguso, R. T., & Bernstein, B. E.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Manguso, Robert T.
- Bernstein, Bradley E.
- ORCID
- Griffin, Gabriel K.
- Wu, Jingyi
- Iracheta-Vellve, Arvin
- Patti, James C.
- Hsu, Jeffrey
- Dele-Oni, Deborah
- Du, Peter P.
- Halawi, Aya G.
- Ishizuka, Jeffrey J.
- Kim, Sarah Y.
- Klaeger, Susan
- Knudsen, Nelson H.
- Miller, Brian C.
- Nguyen, Tung H.
- Olander, Kira E.
- Papanastasiou, Malvina
- Rachimi, Suzanna
- Robitschek, Emily J.
- Schneider, Emily M.
- Yeary, Mitchell D.
- Zimmer, Margaret D.
- Jaffe, Jacob D.
- Carr, Steven A.
- Doench, John G.
- Haining, W. Nicholas
- Yates, Kathleen B.
- Manguso, Robert T.
- Bernstein, Bradley E.
- Venue
- Nature
- Published
- 2021-05-05
- Volume
- 595
- Issue
- 7866
- Pages
- 309-314
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9166167
- OpenAlex
- W3158155618
- Cited by
- 370
- References
- 61
- Citations by year
- 2026: 57 · 2025: 78 · 2024: 77 · 2023: 69 · 2022: 70 · 2021: 19
- FWCI
- 21.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (DP1CA216873, K08CA245112, U24CA210986, U01CA214125)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- SETDB1, H3K9 methyltransferase, epigenetic silencing, tumor immunogenicity, immune evasion, immune checkpoint blockade, transposable elements, segmental duplication, retroviral antigens, cytotoxic T lymphocytes, HUSH complex, chromatin regulators, immunotherapy targets
- MeSH terms
- Animals, Antigens, Viral, Chromatin, Disease Models, Animal, DNA Transposable Elements, Female, Humans, Neoplasms, Histone-Lysine N-Methyltransferase, T-Lymphocytes, Cytotoxic, Histocompatibility Antigens Class I, Gene Silencing, Mice, Programmed Cell Death 1 Receptor, CRISPR-Cas Systems
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