title: Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype.
abstract: Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488-97. ©2016 AACR.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Run
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Bergin
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Slater
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Xianglan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Judd
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: En-Ju D
authors.initials: ED
authors.lastname: Lin
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Widstrom
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Scoville
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210.|The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D059647:Gene-Environment Interaction; D006799:Housing, Animal; D007031:Hypothalamus / Q000378:metabolism*; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011433:Propranolol / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D000319:Adrenergic beta-Antagonists; D019208:Brain-Derived Neurotrophic Factor; D011433:Propranolol