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 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.

Biomaterials and oxygen join forces to shape the immune response and boost SARS-CoV-2 vaccines

“…1A). Our results indicated that hypoxic conditions of the subcutaneously injected cryogel suppress DC activation, which is consistent with previous reports 15,16 . Therefore, we engineered oxygen-generating cryogels (O 2 -Cryogels) to mitigate hypoxia-driven immunosuppression 17 .…”

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

“…With respect to dendritic cells (DCs), contradictory effects of hypoxic TME with excessive ROS have been reported [94]. Despite the effect of hypoxia and ROS in the upregulation of a plethora of pro-inflammatory cytokines, both hypoxia and ROS stimulate migration of immature but prevent migration of mature-DCs resulting in an immunosuppressive TME.…”

“…Despite the effect of hypoxia and ROS in the upregulation of a plethora of pro-inflammatory cytokines, both hypoxia and ROS stimulate migration of immature but prevent migration of mature-DCs resulting in an immunosuppressive TME. These lead to limited influx and maturation of immature DCs to the TME while the egress of activated DCs to lymphoid system is prevented, limiting the function of DCs in presenting tumor antigens to activate T lymphocytes, [94].…”

Hyaluronic acid optimizes therapeutic effects of Hydrogen peroxide-induced oxidative stress on breast cancer

“…Nonetheless, systemic or local administration alone has not succeeded to eliminate tumours, and the mechanism by which hydrogen peroxide therapy produces anti-tumour effects is still debated. Owing to the homeostatic role of immune cells in maintaining the integrity of every tissue, these cells tend to localize at the tumour loci (26). Subsequently, immune cells adapt to the hypoxic conditions found in the tumour microenvironment and can protect and support cancerous tissues and tumour cells (27,28).…”