KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements

Shang-Min Zhang, Wesley L. Cai, Xiaoni Liu, Durga Thakral, Jiesi Luo, Lok Hei Chan, Meaghan K. McGeary, Eric Song, Kim R. M. Blenman, Goran Micevic, Shlomit Jessel, Yangyi Zhang, Mingzhu Yin, Carmen J. Booth, Lucia B. Jilaveanu, William Damsky, Mario Sznol, Harriet M. Kluger, Akiko Iwasaki, Marcus W. Bosenberg () and Qin Yan ()
Additional contact information
Shang-Min Zhang: Yale School of Medicine
Wesley L. Cai: Yale School of Medicine
Xiaoni Liu: Yale School of Medicine
Durga Thakral: Yale School of Medicine
Jiesi Luo: Yale School of Medicine
Lok Hei Chan: Yale School of Medicine
Meaghan K. McGeary: Yale School of Medicine
Eric Song: Yale School of Medicine
Kim R. M. Blenman: Yale School of Medicine
Goran Micevic: Yale School of Medicine
Shlomit Jessel: Yale School of Medicine
Yangyi Zhang: Yale School of Medicine
Mingzhu Yin: Yale School of Medicine
Carmen J. Booth: Yale School of Medicine
Lucia B. Jilaveanu: Yale School of Medicine
William Damsky: Yale School of Medicine
Mario Sznol: Yale School of Medicine
Harriet M. Kluger: Yale School of Medicine
Akiko Iwasaki: Yale School of Medicine
Marcus W. Bosenberg: Yale School of Medicine
Qin Yan: Yale School of Medicine

Nature, 2021, vol. 598, issue 7882, 682-687

Abstract: Abstract Tumours use various strategies to evade immune surveillance1,2. Immunotherapies targeting tumour immune evasion such as immune checkpoint blockade have shown considerable efficacy on multiple cancers3,4 but are ineffective for most patients due to primary or acquired resistance5–7. Recent studies showed that some epigenetic regulators suppress anti-tumour immunity2,8–12, suggesting that epigenetic therapies could boost anti-tumour immune responses and overcome resistance to current immunotherapies. Here we show that, in mouse melanoma models, depletion of KDM5B—an H3K4 demethylase that is critical for melanoma maintenance and drug resistance13–15—induces robust adaptive immune responses and enhances responses to immune checkpoint blockade. Mechanistically, KDM5B recruits the H3K9 methyltransferase SETDB1 to repress endogenous retroelements such as MMVL30 in a demethylase-independent manner. Derepression of these retroelements activates cytosolic RNA-sensing and DNA-sensing pathways and the subsequent type-I interferon response, leading to tumour rejection and induction of immune memory. Our results demonstrate that KDM5B suppresses anti-tumour immunity by epigenetic silencing of retroelements. We therefore reveal roles of KDM5B in heterochromatin regulation and immune evasion in melanoma, opening new paths for the development of KDM5B-targeting and SETDB1-targeting therapies to enhance tumour immunogenicity and overcome immunotherapy resistance.

Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (5)

Downloads: (external link)
https://www.nature.com/articles/s41586-021-03994-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:598:y:2021:i:7882:d:10.1038_s41586-021-03994-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-021-03994-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().