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Cancer Immunol Immunother. 2016 Oct;65(10):1159-67. doi: 10.1007/s00262-016-1879-5. Epub 2016 Aug 6.

Inhibition of HIF-1α enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer.

Author information

1
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
2
Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
3
Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
4
Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
5
Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
6
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
7
Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. hajatij@sina.tums.ac.ir.

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.

KEYWORDS:

Cancer; Dendritic cell-based immunotherapy; HIF-1α; Hypoxia

PMID:
27497816
DOI:
10.1007/s00262-016-1879-5
[Indexed for MEDLINE]

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