title: Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells.
abstract: Cancer immunotherapy has shown great promise as a new standard cancer therapeutic modality. However, the response rates are limited for current approach that depends on enhancing spontaneous antitumor immune responses. Therefore, increasing tumor immunogenicity by expressing appropriate cytokines should further improve the current immunotherapy. IL-33 is a member of the IL-1 family of cytokines and is released by necrotic epithelial cells or activated innate immune cells and is thus considered a "danger" signal. The role of IL-33 in promoting type 2 immune responses and tissue inflammation has been well established. However, whether IL-33 drives antitumor immune responses is controversial. Our previous work established that IL-33 promoted the function of CD8(+) T cells. In this study, we showed that the expression of IL-33 in two types of cancer cells potently inhibited tumor growth and metastasis. Mechanistically, IL-33 increased numbers and IFN-γ production by CD8(+) T and NK cells in tumor tissues, thereby inducing a tumor microenvironment favoring tumor eradication. Importantly, IL-33 greatly increased tumor Ag-specific CD8(+) T cells. Furthermore, both NK and CD8(+) T cells were required for the antitumor effect of IL-33. Moreover, depletion of regulatory T cells worked synergistically with IL-33 expression for tumor elimination. Our studies established "alarmin" IL-33 as a promising new cytokine for tumor immunotherapy through promoting cancer-eradicating type 1 immune responses.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, People's Republic of China;
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, People's Republic of China; Department of Biochemistry and Molecular Biology, Soochow University, Suzhou 215007, People's Republic of China;
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Guangdong Key Laboratory for Emerging Infectious Disease, Shenzhen Key Laboratory of Infection and Immunity, Third People's Hospital, Guangdong Medical College, Shenzhen, Guangdong 518112, China;
authors.forename: Qianting
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; The First Affiliated Hospital, Soochow University, Suzhou 215006, People's Republic of China;
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, People's Republic of China;
authors.forename: Wen
authors.initials: W
authors.lastname: Wen
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, People's Republic of China;
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Key Laboratory of Cryogenics, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Haidian District, Beijing 100190, People's Republic of China;
authors.forename: Junfeng
authors.initials: J
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China;
authors.forename: Wenxin
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, People's Republic of China;
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qi
authors.affiliation: Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, People's Republic of China;
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.affiliation: The Third Affiliated Hospital, Soochow University, Changzhou 213003, China;
authors.forename: Jingting
authors.initials: J
authors.lastname: Jiang
authors.affiliation: The Third Affiliated Hospital, Soochow University, Changzhou 213003, China;
authors.forename: Changping
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, People's Republic of China;
authors.forename: Xueguang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Guangdong Key Laboratory for Emerging Infectious Disease, Shenzhen Key Laboratory of Infection and Immunity, Third People's Hospital, Guangdong Medical College, Shenzhen, Guangdong 518112, China;
authors.forename: Xinchun
authors.initials: X
authors.lastname: Chen
authors.affiliation: Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and.
authors.forename: Heth
authors.initials: H
authors.lastname: Turnquist
authors.affiliation: Department of Immunology, Institute of Medical Biotechnology, Soochow University, Suzhou 215007, People's Republic of China;
authors.forename: Yibei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232 binfeng@pitt.edu xlyb99@163.com.
authors.forename: Binfeng
authors.initials: B
authors.lastname: Lu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D007167:Immunotherapy; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D000067596:Interleukin-33 / Q000096:biosynthesis / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D018664:Interleukin-12; D007371:Interferon-gamma