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

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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.

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Abbreviations

BMDC:

Bone marrow-derived dendritic cell

DI:

Division index

GrB:

Granzyme B

HIF-1:

Hypoxia-inducible factor

HRE:

Hypoxia response element

PVDF:

Polyvinylidene difluoride

Treg:

Regulatory T cell

VEGF:

Vascular endothelial growth factor

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Authors and Affiliations

  1. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Nasim Kheshtchin, Reza Mirzaei, Afshin Namdar, Farshid Noorbakhsh & Jamshid Hadjati

  2. Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Samaneh Arab

  3. Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Maryam Ajami

  4. Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

    Mahboubeh Ashourpour, Najmeh Khosravianfar & Farhad Jadidi-Niaragh

  5. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Neda Mousavi & Farhad Jadidi-Niaragh

  6. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Farhad Jadidi-Niaragh

Authors
  1. Nasim Kheshtchin
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  2. Samaneh Arab
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  3. Maryam Ajami
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  4. Reza Mirzaei
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Correspondence to Jamshid Hadjati.

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Kheshtchin, N., Arab, S., Ajami, M. et al. Inhibition of HIF-1α enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer. Cancer Immunol Immunother 65, 1159–1167 (2016). https://doi.org/10.1007/s00262-016-1879-5

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  • DOI: https://doi.org/10.1007/s00262-016-1879-5

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