KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements.

Autor: Zhang SM; Department of Pathology, Yale School of Medicine, New Haven, CT, USA., Cai WL; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.; Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Liu X; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA., Thakral D; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA., Luo J; Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA.; Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA., Chan LH; Department of Pathology, Yale School of Medicine, New Haven, CT, USA., McGeary MK; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA., Song E; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA., Blenman KRM; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.; Department of Medicine, Yale School of Medicine, New Haven, CT, USA.; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Micevic G; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA., Jessel S; Department of Medicine, Yale School of Medicine, New Haven, CT, USA., Zhang Y; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.; Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China., Yin M; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.; Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Hospital, Central South University, Changsha, China., Booth CJ; Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA., Jilaveanu LB; Department of Medicine, Yale School of Medicine, New Haven, CT, USA.; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Damsky W; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Sznol M; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA., Kluger HM; Department of Medicine, Yale School of Medicine, New Haven, CT, USA.; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.; Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA., Iwasaki A; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.; Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA.; Howard Hughes Medical Institute, Chevy Chase, MD, USA., Bosenberg MW; Department of Pathology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.; Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.; Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.; Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.; Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu., Yan Q; Department of Pathology, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.; Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.; Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.; Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Oct; Vol. 598 (7882), pp. 682-687. Date of Electronic Publication: 2021 Oct 20.
DOI: 10.1038/s41586-021-03994-2
Abstrakt: 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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