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Hypoxia-/HIF-1α-Driven Factors of the Tumor Microenvironment Impeding Antitumor Immune Responses and Promoting Malignant Progression

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Oxygen Transport to Tissue XL

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1072))

Abstract

The metabolic tumor microenvironment (TME) is characterized inter alia by critical oxygen depletion (hypoxia/anoxia), extracellular acidosis (pH ≤ 6.8), high lactate levels (up to 40 mM in heterogeneously distributed areas), strongly elevated adenosine concentrations (10–100 μM) and declining nutrient resources. These TME features are major drivers, e.g., for genetic instability, intratumor heterogeneity, malignant progression and development of resistance to conventional anticancer therapies. In this context, hypoxia-dependent (and non-hypoxic) HIF-1α activation plays a key role in orchestrating a multifaceted (local) suppression of innate and adaptive antitumor immune responses (and of immune-based tumor treatment). Besides the characteristic traits mentioned, the immune-suppressive actions can additionally be triggered by an (over-)expression of VEGF and activation of VEGFR, and externalisation of phosphatidylserine from the inner to the outer membrane leaflet of cells and exosomes. Altogether, and even individually, these features provide strong immune-suppressive signals. The downstream effects of an enhanced HIF-1α expression include (a) an activation of immune-suppressive effects (recruitment and stimulation of immune-suppressor cells [e.g., Treg, MDSC], secretion of immune-suppressive TH2-type cytokines), and (b) inhibition of antitumor immune responses (inhibition of immune cell actions [e.g., NK, NKT, CD4+, CD8+], inhibition of antigen-presenting cells [e.g., DC], reduced production of immune-stimulatory TH1-type cytokines).

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Abbreviations

A2AR, A2BR:

Adenosine receptors

ADO:

Adenosine

ATP:

Adenosine triphosphate

cAMP:

Cyclic adenosine monophosphate

CD39:

Ectonucleoside triphosphate diphosphohydrolase 1

CD4+ :

Helper T cell

CD73:

Ecto 5′-nucleotidase

CD8+ :

Cytoxic T cell

DC:

Dendritic cell

ENT-1:

Equilibrative nucleoside transporter 1

GPR81:

G-protein receptor 81 (= cell surface lactate receptor)

Gs, Gi :

Stimulatory/inhibitory G-proteins

HCA 1:

Hydroxycarboxylic acid receptor 1 (syn. GPR81)

HIF:

Hypoxia-inducible (transcription) factor

IFN-γ:

Interferon γ

IL:

Interleukin

LDH:

Lactate dehydrogenase A

MDSC:

Myeloid-derived suppressor cell

mTOR:

Mechanistic (“mammalian”) target of rapamycin

MΦ:

Macrophage

NK:

Natural killer cell

NKT:

Natural killer like T cell

PANX:

Pannexin (ATP channel)

PDL1:

Programmed cell death 1 protein ligand

pO2 :

Oxygen partial pressure

PS:

Phosphatidylserine

TGF-β:

Transforming growth factor β

TH:

T helper cell

TIM:

T cell immunoglobulin and mucin domain (PS surface receptor)

TME :

Tumor microenvironment

TNF-α:

Tumor necrosis factor α

Treg:

Regulatory T cell

VEGF:

Vascular endothelial growth factor

VEGF-R:

VEGF receptor

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Author information

Authors and Affiliations

  1. Department of Radiation Oncology and Radiotherapy, Klinikum rechts der Isar, Technical University of Munich (TUM), Munich, Germany

    Peter Vaupel

  2. Center of Translational Cancer Research (TranslaTUM), Technical University of Munich, Campus Klinikum rechts der Isar, Munich, Germany

    Gabriele Multhoff

Authors
  1. Peter Vaupel
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  2. Gabriele Multhoff
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Corresponding author

Correspondence to Peter Vaupel .

Editor information

Editors and Affiliations

  1. Julius Bernstein Institute of Physiology, Martin Luther University, Halle-Wittenberg, Halle/Saale, Germany

    Oliver Thews

  2. Department of Physiology & Biophysics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA

    Joseph C. LaManna

  3. Microvascular Measurements, St. Lorenzen, Italy

    David K. Harrison

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Vaupel, P., Multhoff, G. (2018). Hypoxia-/HIF-1α-Driven Factors of the Tumor Microenvironment Impeding Antitumor Immune Responses and Promoting Malignant Progression. In: Thews, O., LaManna, J., Harrison, D. (eds) Oxygen Transport to Tissue XL. Advances in Experimental Medicine and Biology, vol 1072. Springer, Cham. https://doi.org/10.1007/978-3-319-91287-5_27

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