Abstract
In order to compensate for the increased oxygen consumption in growing tumors, tumors need angiogenesis and vasculogenesis to increase the supply. Insufficiency in this process or in the microcirculation leads to hypoxic tumor areas with a significantly reduced pO2, which in turn leads to alterations in the biology of cancer cells as well as in the tumor microenvironment. Cancer cells develop more aggressive phenotypes, stem cell features and are more prone to metastasis formation and migration. In addition, intratumoral hypoxia confers therapy resistance, specifically radioresistance. Reactive oxygen species are crucial in fixing DNA breaks after ionizing radiation. Thus, hypoxic tumor cells show a two- to threefold increase in radioresistance. The microenvironment is enriched with chemokines (e.g., SDF-1) and growth factors (e.g., TGFβ) additionally reducing radiosensitivity. During recent years hypoxia has also been identified as a major factor for immune suppression in the tumor microenvironment. Hypoxic tumors show increased numbers of myeloid derived suppressor cells (MDSCs) as well as regulatory T cells (Tregs) and decreased infiltration and activation of cytotoxic T cells. The combination of radiotherapy with immune checkpoint inhibition is on the rise in the treatment of metastatic cancer patients, but is also tested in multiple curative treatment settings. There is a strong rationale for synergistic effects, such as increased T cell infiltration in irradiated tumors and mitigation of radiation-induced immunosuppressive mechanisms such as PD-L1 upregulation by immune checkpoint inhibition. Given the worse prognosis of patients with hypoxic tumors due to local therapy resistance but also increased rate of distant metastases and the strong immune suppression induced by hypoxia, we hypothesize that the subgroup of patients with hypoxic tumors might be of special interest for combining immune checkpoint inhibition with radiotherapy.
Highlights
Solid tumors are prone to encounter chronic or intermittent hypoxic microenvironment
Master regulators of metabolic reprogramming under hypoxia are the O2-sensitive hypoxia-inducible transcription factors (HIFs), the cellular nutrient sensing mTOR and the energysensing AMP kinase, as well as the unfolded protein response
Cancer cells under hypoxic conditions show a downregulation of MHC class-I molecules [94] (Figure 1), which are crucial for the immune recognition and immune mediated lysis of tumor cells [95]
Summary
Solid tumors are prone to encounter chronic or intermittent hypoxic microenvironment. Master regulators of metabolic reprogramming under hypoxia are the O2-sensitive hypoxia-inducible transcription factors (HIFs), the cellular nutrient sensing mTOR and the energysensing AMP kinase, as well as the unfolded protein response They induce downregulation of anabolic metabolism, upregulation of nutrient import and glycolysis, a switch from oxidative phosphorylation to lactic acid fermentation, upregulation of acid extrusion pathways such as monocarboxylate transport, adaptation of glutamine metabolisms to maintain fuelling of the citrate pool, alteration of lipid metabolism, attenuation of mitochondrial reactive oxygen species (ROS) formation and/or up-regulation of oxidative defense [for recent reviews [4, 16, 17]]. Beyond malignant progression and immune evasion, hypoxia confers resistance to chemo- [2] and radiation therapy as described in the paragraphs
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