Open AccessKDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements
Author(s) -
ShangMin Zhang,
Wesley L. Cai,
Xiaoni Liu,
Durga Thakral,
Jiesi Luo,
Lok-Hei Chan,
Meaghan K. McGeary,
Eric Song,
Kim 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,
Qin Yan
Publication year - 2021
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-021-03994-2
Subject(s) - immune system , demethylase , biology , epigenetics , cancer research , immune checkpoint , immunotherapy , immunology , genetics , gene
Tumours use various strategies to evade immune surveillance 1,2 . Immunotherapies targeting tumour immune evasion such as immune checkpoint blockade have shown considerable efficacy on multiple cancers 3,4 but are ineffective for most patients due to primary or acquired resistance 5-7 . Recent studies showed that some epigenetic regulators suppress anti-tumour immunity 2,8-12 , 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 resistance 13-15 -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.