Oxygen in the tumor microenvironment: effects on dendritic cell function

Abstract

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 T_h17 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.

Keywords: dendritic cells; extracellular vesicles; hypoxia; reactive oxygen species; tumor microenvironment.

Figure 1. Targets and sources of ROS in DCs

(Left) ROS can attack both mono- and poly-unsaturated lipids in membranes, causing endosomal leakage and loss of pH and electron gradients. Cysteine residues on proteins can oxidize, resulting in the formation of disulfide bridges or a stepwise oxidation to sulfonic acid. This can activate redox-sensitive signaling factors, but also block enzymatic activity or cause protein misfolding. Finally, both free and DNA-helix incorporated guanine nucleotides can oxidize, leading to GC-TA or GC-CG transversion mutations. (Right) Sources of ROS for DCs in the TME: increased NOX (NAD(P)H oxidase) activity, ER stress due to the unfolded protein response, β-oxidation of fatty acids, abrogated electron transfer in mitochondria and uptake of ROS-containing tumor-derived EVs.

Figure 2. Combined effects of ROS and hypoxia in the TME

ROS promote DC maturation, antigen cross-presentation, DC migration and CD8⁺ T cell responses needed for anti-tumor immunity. In contrast, hypoxia can both lower or increase DC maturation and skews T cell responses towards a tolerogenic T_h17 response. Moreover, hypoxia can inhibit ingress of immature DCs into the tumor whilst blocking migration of mature DCs from the tumor to draining lymph nodes. Hypoxia does however promote secretion of various inflammatory cytokines such as TNF-α.