title: Inhibition of HIF-1α enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer.
abstract: Considerable evidence shows that the tumor microenvironment is an active participant in preventing immunosurveillance and limiting the efficacy of anticancer therapies. Hypoxia is a prominent characteristic of the solid tumor microenvironment. The transcription factor hypoxia-inducible factor-1α (HIF-1α) is an important mediator of hypoxic response of tumor cells that modulates the expression of specific genes involved in tumor immunosuppression. Using a 4T1 breast cancer model, we show that in vivo administration of PX-478, an inhibitor of oxygen-sensitive HIF-1α, led to reduced expression of Foxp3 and VEGF transcript and/or protein, molecules that are directly controlled by HIF-1. When combined with dendritic cell (DC)-based vaccination, HIF-1α inhibition resulted in an augmented cytotoxic T lymphocyte effector function, improved proliferation status of T cells, increased production of inflammatory cytokine IFN-γ, as well as reduced regulatory function of T cells in association with slower tumor growth. Taken together, our findings indicate that the use of HIF-1α inhibition provides an immune adjuvant activity, thereby improves the efficacy of tumor antigen-based DC vaccine.
authors: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Nasim
authors: N
authors: Kheshtchin
authors: Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Samaneh
authors: S
authors: Arab
authors: Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors: Maryam
authors: M
authors: Ajami
authors: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Reza
authors: R
authors: Mirzaei
authors: Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
authors: Mahboubeh
authors: M
authors: Ashourpour
authors: Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
authors: Neda
authors: N
authors: Mousavi
authors: Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
authors: Najmeh
authors: N
authors: Khosravianfar
authors: Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.|Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.|Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
authors: Farhad
authors: F
authors: Jadidi-Niaragh
authors: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Afshin
authors: A
authors: Namdar
authors: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
authors: Farshid
authors: F
authors: Noorbakhsh
authors: Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. hajatij@sina.tums.ac.ir.
authors: Jamshid
authors: J
authors: Hadjati
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000628:therapy*; D019496:Cancer Vaccines / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors*; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009150:Mustard Compounds / Q000627:therapeutic use*; D010666:Phenylpropionates / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009150:Mustard Compounds; D010666:Phenylpropionates; D042461:Vascular Endothelial Growth Factor A; D007371:Interferon-gamma
keywords: Cancer; Dendritic cell-based immunotherapy; HIF-1α; Hypoxia