Implications of Hyperoxia over the Tumor Microenvironment: An Overview Highlighting the Importance of the Immune System

Abstract

Hyperoxia is used in order to counteract hypoxia effects in the TME (tumor microenvironment), which are described to boost the malignant tumor phenotype and poor prognosis. The reduction of tumor hypoxic state through the formation of a non-aberrant vasculature or an increase in the toxicity of the therapeutic agent improves the efficacy of therapies such as chemotherapy. Radiotherapy efficacy has also improved, where apoptotic mechanisms seem to be implicated. Moreover, hyperoxia increases the antitumor immunity through diverse pathways, leading to an immunopermissive TME. Although hyperoxia is an approved treatment for preventing and treating hypoxemia, it has harmful side-effects. Prolonged exposure to high oxygen levels may cause acute lung injury, characterized by an exacerbated immune response, and the destruction of the alveolar-capillary barrier. Furthermore, under this situation, the high concentration of ROS may cause toxicity that will lead not only to cell death but also to an increase in chemoattractant and proinflammatory cytokine secretion. This would end in a lung leukocyte recruitment and, therefore, lung damage. Moreover, unregulated inflammation causes different consequences promoting tumor development and metastasis. This process is known as protumor inflammation, where different cell types and molecules are implicated; for instance, IL-1β has been described as a key cytokine. Although current results show benefits over cancer therapies using hyperoxia, further studies need to be conducted, not only to improve tumor regression, but also to prevent its collateral damage.

Keywords: hyperoxia; hypoxia; immunotherapy; inflammation; tumor microenvironment.

Figure 1

Median percentage oxygen in human tumors and related normal tissues.

Figure 2

Hyperoxia treatment effect over the immune response. The adenosinergic pathway is altered, presenting a modification in the activity of the effector and regulatory T cells. MDSC recruitment and activity are modified, while PMNs are altered, leading to an immunopermissive TME.

Figure 3

GO terms from biological processes found to be mainly modified following the gene enrichment analysis.

Figure 4

Volcano plot representation of the main genes whose expression significantly changed under hyperoxic conditions in (a) uveal melanoma cell line (MUM2B) and (b) normal human bronchial epithelial cells (HBEC3-KT) (Figure S1).