Skip to main content
Erschienen in: Cancer Immunology, Immunotherapy 10/2016

06.08.2016 | Original Article

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

verfasst von: Nasim Kheshtchin, Samaneh Arab, Maryam Ajami, Reza Mirzaei, Mahboubeh Ashourpour, Neda Mousavi, Najmeh Khosravianfar, Farhad Jadidi-Niaragh, Afshin Namdar, Farshid Noorbakhsh, Jamshid Hadjati

Erschienen in: Cancer Immunology, Immunotherapy | Ausgabe 10/2016

Einloggen, um Zugang zu erhalten

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.
Literatur
1.
Zurück zum Zitat Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4:437–447CrossRefPubMed Brown JM, Wilson WR (2004) Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 4:437–447CrossRefPubMed
2.
3.
Zurück zum Zitat 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 475:226–230CrossRefPubMed 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 475:226–230CrossRefPubMed
4.
Zurück zum Zitat Sitkovsky M, Lukashev D (2005) Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors. Nat Rev Immunol 5:712–721CrossRefPubMed Sitkovsky M, Lukashev D (2005) Regulation of immune cells by local-tissue oxygen tension: HIF1α and adenosine receptors. Nat Rev Immunol 5:712–721CrossRefPubMed
5.
Zurück zum Zitat Noman MZ, Benlalam H, Hasmim M, Chouaib S (2011) Cytotoxic T cells–stroma interactions. Bull Cancer 98:E19–E24PubMed Noman MZ, Benlalam H, Hasmim M, Chouaib S (2011) Cytotoxic T cells–stroma interactions. Bull Cancer 98:E19–E24PubMed
6.
Zurück zum Zitat 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 71:5976–5986CrossRefPubMed 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 71:5976–5986CrossRefPubMed
7.
Zurück zum Zitat 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 31:357–377CrossRefPubMed 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 31:357–377CrossRefPubMed
9.
10.
Zurück zum Zitat Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634CrossRefPubMed Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–634CrossRefPubMed
11.
Zurück zum Zitat Kim JW, Gao P, Dang CV (2007) Effects of hypoxia on tumor metabolism. Cancer Metastasis Rev 26:291–298CrossRefPubMed Kim JW, Gao P, Dang CV (2007) Effects of hypoxia on tumor metabolism. Cancer Metastasis Rev 26:291–298CrossRefPubMed
12.
13.
Zurück zum Zitat 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 7:90–100CrossRefPubMed 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 7:90–100CrossRefPubMed
14.
Zurück zum Zitat Macpherson GR, Figg WD (2004) Small molecule-mediated anti-cancer therapy via hypoxia-inducible factor-1 blockade. Cancer Biol Ther 3:503–504CrossRefPubMed Macpherson GR, Figg WD (2004) Small molecule-mediated anti-cancer therapy via hypoxia-inducible factor-1 blockade. Cancer Biol Ther 3:503–504CrossRefPubMed
15.
Zurück zum Zitat 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 3:233–244CrossRefPubMed 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 3:233–244CrossRefPubMed
16.
Zurück zum Zitat 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 178:479–488CrossRefPubMed 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 178:479–488CrossRefPubMed
17.
Zurück zum Zitat 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 208:1367–1376CrossRefPubMedPubMedCentral 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 208:1367–1376CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat 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–E2793CrossRefPubMedPubMedCentral 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–E2793CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Takenaga K (2011) Angiogenic signaling aberrantly induced by tumor hypoxia. Front Biosci (Landmark Ed) 16:31–48CrossRef Takenaga K (2011) Angiogenic signaling aberrantly induced by tumor hypoxia. Front Biosci (Landmark Ed) 16:31–48CrossRef
20.
Zurück zum Zitat 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 182:3510–3521CrossRefPubMed 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 182:3510–3521CrossRefPubMed
21.
Zurück zum Zitat 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 198:783–796CrossRefPubMedPubMedCentral 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 198:783–796CrossRefPubMedPubMedCentral
22.
Zurück zum Zitat 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 204:1257–1265CrossRefPubMedPubMedCentral 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 204:1257–1265CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat 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 111:251–259CrossRefPubMedPubMedCentral 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 111:251–259CrossRefPubMedPubMedCentral
24.
Zurück zum Zitat 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 211:781–790CrossRefPubMedPubMedCentral 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 211:781–790CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat 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 167:6140–6149CrossRefPubMed 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 167:6140–6149CrossRefPubMed
26.
Zurück zum Zitat 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 14:1173–1182CrossRefPubMedPubMedCentral 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 14:1173–1182CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Barsoum IB, Smallwood CA, Siemens DR, Graham CH (2014) A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 74:665–674CrossRefPubMed Barsoum IB, Smallwood CA, Siemens DR, Graham CH (2014) A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res 74:665–674CrossRefPubMed
28.
Zurück zum Zitat 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 72:4629–4641CrossRefPubMed 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 72:4629–4641CrossRefPubMed
29.
Zurück zum Zitat 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:e853CrossRefPubMedPubMedCentral 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:e853CrossRefPubMedPubMedCentral
30.
Zurück zum Zitat Sitkovsky MV (2009) T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol 30:102–108CrossRefPubMed Sitkovsky MV (2009) T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol 30:102–108CrossRefPubMed
31.
Zurück zum Zitat 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 42:1197–1211CrossRefPubMed 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 42:1197–1211CrossRefPubMed
Metadaten
Titel
Inhibition of HIF-1α enhances anti-tumor effects of dendritic cell-based vaccination in a mouse model of breast cancer
verfasst von
Nasim Kheshtchin
Samaneh Arab
Maryam Ajami
Reza Mirzaei
Mahboubeh Ashourpour
Neda Mousavi
Najmeh Khosravianfar
Farhad Jadidi-Niaragh
Afshin Namdar
Farshid Noorbakhsh
Jamshid Hadjati
Publikationsdatum
06.08.2016
Verlag
Springer Berlin Heidelberg
Erschienen in
Cancer Immunology, Immunotherapy / Ausgabe 10/2016
Print ISSN: 0340-7004
Elektronische ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-016-1879-5

Weitere Artikel der Ausgabe 10/2016

Cancer Immunology, Immunotherapy 10/2016 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.