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

Cancer Immunology, Immunotherapy volume 65, pages 1159–1167 (2016)Cite this article

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

References

  1. Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4:437–447

    CAS  Article  PubMed  Google Scholar 

  2. Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–296

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A, Wang LP et al (2011) Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475:226–230

    CAS  Article  PubMed  Google Scholar 

  4. Sitkovsky M, Lukashev D (2005) Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors. Nat Rev Immunol 5:712–721

    CAS  Article  PubMed  Google Scholar 

  5. Noman MZ, Benlalam H, Hasmim M, Chouaib S (2011) Cytotoxic T cells–stroma interactions. Bull Cancer 98:E19–E24

    PubMed  Google Scholar 

  6. Noman MZ, Janji B, Kaminska B, Van Moer K, Pierson S, Przanowski P et al (2011) Blocking hypoxia-induced autophagy in tumors restores cytotoxic T-cell activity and promotes regression. Cancer Res 71:5976–5986

    CAS  Article  PubMed  Google Scholar 

  7. Noman MZ, Messai Y, Carre T, Akalay I, Meron M, Janji B et al (2011) Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumor progression and antitumor response. Crit Rev Immunol 31:357–377

    CAS  Article  PubMed  Google Scholar 

  8. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732

    CAS  Article  PubMed  Google Scholar 

  9. Shi YH, Fang WG (2004) Hypoxia-inducible factor-1 in tumour angiogenesis. World J Gastroenterol 10:1082–1087

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634

    CAS  Article  PubMed  Google Scholar 

  11. Kim JW, Gao P, Dang CV (2007) Effects of hypoxia on tumor metabolism. Cancer Metastasis Rev 26:291–298

    Article  PubMed  Google Scholar 

  12. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11:393–410

    CAS  Article  PubMed  Google Scholar 

  13. Koh MY, Spivak-Kroizman T, Venturini S, Welsh S, Williams RR, Kirkpatrick DL et al (2008) Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1alpha. Mol Cancer Ther 7:90–100

    CAS  Article  PubMed  Google Scholar 

  14. Macpherson GR, Figg WD (2004) Small molecule-mediated anti-cancer therapy via hypoxia-inducible factor-1 blockade. Cancer Biol Ther 3:503–504

    CAS  Article  PubMed  Google Scholar 

  15. Welsh S, Williams R, Kirkpatrick L, Paine-Murrieta G, Powis G (2004) Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. Mol Cancer Ther 3:233–244

    CAS  Article  PubMed  Google Scholar 

  16. Inaba K, Inaba M, Naito M, Steinman RM (1993) Dendritic cell progenitors phagocytose particulates, including bacillus Calmette-Guerin organisms, and sensitize mice to mycobacterial antigens in vivo. J Exp Med 178:479–488

    CAS  Article  PubMed  Google Scholar 

  17. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR et al (2011) HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T H 17 and T reg cells. J Exp Med 208:1367–1376

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P et al (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 109:E2784–E2793

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Takenaga K (2011) Angiogenic signaling aberrantly induced by tumor hypoxia. Front Biosci (Landmark Ed) 16:31–48

    CAS  Article  Google Scholar 

  20. Noman MZ, Buart S, Van Pelt J, Richon C, Hasmim M, Leleu N et al (2009) The cooperative induction of hypoxia-inducible factor-1 alpha and STAT3 ring hypoxia induced an impairment of tumor susceptibility to CTL-mediated cell lysis. J Immunol 182:3510–3521

    CAS  Article  PubMed  Google Scholar 

  21. Eltzschig HK, Ibla JC, Furuta GT, Leonard MO, Jacobson KA, Enjyoji K et al (2003) Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J Exp Med 198:783–796

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A et al (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, Linden J et al (2008) A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111:251–259

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P et al (2014) PD-L1 is a novel direct target of HIF-1, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med 211:781–790

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG et al (2001) Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol 167:6140–6149

    CAS  Article  PubMed  Google Scholar 

  26. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E et al (2013) Hypoxia-inducible factors enhance the effector responses of CD8 + T cells to persistent antigen. Nat Immunol 14:1173–1182

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Barsoum IB, Smallwood CA, Siemens DR, Graham CH (2014) A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 74:665–674

    CAS  Article  PubMed  Google Scholar 

  28. Noman MZ, Buart S, Romero P, Ketari S, Janji B, Mari B et al (2012) Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells. Cancer Res 72:4629–4641

    CAS  Article  PubMed  Google Scholar 

  29. Thiel M, Caldwell CC, Kreth S, Kuboki S, Chen P, Smith P et al (2007) Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS ONE 2:e853

    Article  PubMed  PubMed Central  Google Scholar 

  30. Sitkovsky MV (2009) T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol 30:102–108

    CAS  Article  PubMed  Google Scholar 

  31. Helft J, Böttcher J, Chakravarty P, Zelenay S, Huotari J et al (2015) GM-CSF mouse bone marrow cultures comprise a heterogeneous population of CD11c + MHCII + Macrophages and Dendritic Cells. Immunity 42:1197–1211

    CAS  Article  PubMed  Google Scholar 

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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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  5. Mahboubeh Ashourpour
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  7. Najmeh Khosravianfar
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  9. Afshin Namdar
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  10. Farshid Noorbakhsh
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  11. Jamshid Hadjati
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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

Keywords

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