Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.
Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Dongjun
D
Peng
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.|Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Ilona
I
Kryczek
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.|Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Nisha
N
Nagarsheth
Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Lili
L
Zhao
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Shuang
S
Wei
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Weimin
W
Wang
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Yuqing
Y
Sun
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Ende
E
Zhao
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Linda
L
Vatan
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Wojciech
W
Szeliga
The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland.
Jan
J
Kotarski
The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland.
Rafał
R
Tarkowski
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Yali
Y
Dou
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.|The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Kathleen
K
Cho
Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA.
Sharon
S
Hensley-Alford
Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA.
Adnan
A
Munkarah
The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Rebecca
R
Liu
Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.|Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.|The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.|Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Weiping
W
Zou
D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D054370:Chemokine CXCL9 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D020868:Gene Silencing; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008239:Lysine / Q000378:metabolism; D051379:Mice; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011379:Prognosis; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D060890:B7-H1 Antigen; C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; D006657:Histones; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine