Oxygen in the tumor microenvironment: effects on dendritic cell function
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Laurent M. Paardekooper1, Willemijn Vos1 and Geert van den Bogaart1,2
1Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
2Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
Geert van den Bogaart, email: [email protected]
Keywords: tumor microenvironment; dendritic cells; hypoxia; reactive oxygen species; extracellular vesicles
Received: November 14, 2018 Accepted: January 09, 2019 Published: January 25, 2019
Solid tumors grow at a high speed leading to insufficient blood supply to tumor cells. This makes the tumor hypoxic, resulting in the Warburg effect and an increased generation of reactive oxygen species (ROS). Hypoxia and ROS affect immune cells in the tumor micro-environment, thereby affecting their immune function. Here, we review the known effects of hypoxia and ROS on the function and physiology of dendritic cells (DCs). DCs can (cross-)present tumor antigen to activate naive T cells, which play a pivotal role in anti-tumor immunity. ROS might enter DCs via aquaporins in the plasma membrane, diffusion across the plasma membrane or via extracellular vesicles (EVs) released by tumor cells. Hypoxia and ROS exert complex effects on DCs, and can both inhibit and activate maturation of immature DCs. Furthermore, ROS transferred by EVs and/or produced by the DC can both promote antigen (cross-)presentation through phagosomal alkalinization, which preserves antigens by inhibiting proteases, and by direct oxidative modification of proteases. Hypoxia leads to a more migratory and inflammatory DC phenotype. Lastly, hypoxia alters DCs to shift the T- cell response towards a tumor suppressive Th17 phenotype. From numerous studies, the concept is emerging that hypoxia and ROS are mutually dependent effectors on DC function in the tumor micro-environment. Understanding their precise roles and interplay is important given that an adaptive immune response is required to clear tumor cells.
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