1 Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
2 Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
3 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
4 Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA.
5 Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA.
6 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
7 Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
8 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
9 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.
10 Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
11 Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA.
12 Howard Hughes Medical Institute, Chevy Chase, MD, USA.
13 Department of Pathology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
14 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
15 Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
16 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
17 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
18 Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
19 Department of Pathology, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.
20 Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.
21 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.
22 Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.
1 Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
2 Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
3 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
4 Section of Cardiovascular Medicine, Department of Internal Medicine, Yale Cardiovascular Research Center, Yale School of Medicine, New Haven, CT, USA.
5 Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA.
6 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
7 Department of Medicine, Yale School of Medicine, New Haven, CT, USA.
8 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA.
9 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.
10 Department of Comparative Medicine, Yale School of Medicine, New Haven, CT, USA.
11 Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA.
12 Howard Hughes Medical Institute, Chevy Chase, MD, USA.
13 Department of Pathology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
14 Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
15 Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
16 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
17 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
18 Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA. marcus.bosenberg@yale.edu.
19 Department of Pathology, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.
20 Yale Stem Cell Center, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.
21 Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.
22 Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, CT, USA. qin.yan@yale.edu.
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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.
Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).