title: PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer.
abstract: Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy and patient survival. However, the mechanisms underlying effector T-cell trafficking to the tumor microenvironment remain poorly understood in patients with colon cancer. The polycomb repressive complex 2 (PRC2) is involved in cancer progression, but the regulation of tumor immunity by epigenetic mechanisms has yet to be investigated. In this study, we examined the relationship between the repressive PRC2 machinery and effector T-cell trafficking. We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival. Collectively, our findings reveal that PRC2-mediated epigenetic silencing is not only a crucial oncogenic mechanism, but also a key circuit controlling tumor immunosuppression. Therefore, targeting epigenetic programs may have significant implications for improving the efficacy of current cancer immunotherapies relying on effective T-cell-mediated immunity at the tumor site.
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. Graduate Programs in Immunology and Cancer Biology, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Nisha
authors.initials: N
authors.lastname: Nagarsheth
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Dongjun
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. Graduate Programs in Immunology and Cancer Biology, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kryczek
authors.affiliation: Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ende
authors.initials: E
authors.lastname: Zhao
authors.affiliation: Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wei
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Timothy
authors.initials: T
authors.lastname: Frankel
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Linda
authors.initials: L
authors.lastname: Vatan
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Szeliga
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Yali
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan.
authors.forename: Scott
authors.initials: S
authors.lastname: Owens
authors.affiliation: Chemical Biology Laboratory, Center for Cancer Research, NCI-Frederick, Frederick, Maryland.
authors.forename: Victor
authors.initials: V
authors.lastname: Marquez
authors.affiliation: Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Kaixiong
authors.initials: K
authors.lastname: Tao
authors.affiliation: Departments of Colorectal Surgery and Stem Cell Biology and Regenerative Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Emina
authors.initials: E
authors.lastname: Huang
authors.affiliation: Department of Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Guobin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan. Graduate Programs in Immunology and Cancer Biology, University of Michigan School of Medicine, Ann Arbor, Michigan. University of Michigan Comprehensive Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan. wzou@med.umich.edu.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
mesh_terms: D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000235:genetics; D018925:Chemokines / Q000276:immunology*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D044127:Epigenesis, Genetic; D006801:Humans; D063151:Polycomb Repressive Complex 2 / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
chemical_list: D018925:Chemokines; D063151:Polycomb Repressive Complex 2