The Role of Hypoxia in Brain Tumor Immune Responses

Abstract

Oxygen is a vital component of living cells. Low levels of oxygen in body tissues, known as hypoxia, can affect multiple cellular functions across a variety of cell types and are a hallmark of brain tumors. In the tumor microenvironment, abnormal vasculature and enhanced oxygen consumption by tumor cells induce broad hypoxia that affects not only tumor cell characteristics but also the antitumor immune system. Although some immune reactions require hypoxia, hypoxia generally negatively affects immunity. Hypoxia induces tumor cell invasion, cellular adaptations to hypoxia, and tumor cell radioresistance. In addition, hypoxia limits the efficacy of immunotherapy and hinders antitumor responses. Therefore, understanding the role of hypoxia in the brain tumor, which usually does not respond to immunotherapy alone is important for the development of effective anti-tumor therapies. In this review, we discuss recent evidence supporting the role of hypoxia in the context of brain tumors.

Keywords: Brain neoplasm; Hypoxia; Hypoxia-inducible factor 1; Tumor microenvironment.

Fig. 1. Molecular mechanism of HIF1α degradation and stabilization. Oxygen-dependent PHD activity hydroxylates HIF1α. Hydroxylation of HIF1α allows VHL to bind to HIF1α. VHL facilitates the recruitment of ubiquitin ligases. Ubiquitinated HIF1α is degraded by the proteasome. Hypoxia stabilizes HIF1α. HIF1α translocates to the nucleus and binds to HIF1β. The HIF dimer regulates transcription of HRE genes. HIF1α, hypoxia-inducible factor 1-alpha; PHD, prolyl hydroxylase domain; VHL, von Hippel-Lindau tumor suppressor protein; HRE, hypoxiaresponse element.

Fig. 2. Mechanisms of brain tumor immunity. A: Tumor cell death spreads antigens. Antigen presenting cells uptake antigens and migrate to the lymph node. At the lymph node, antigen presenting cells present antigens to the T cells. T cells undergo clonal expansion and activation. Antigen-specific T cells migrate to the tumor site and kill tumor cells. B: Cytotoxic lymphocytes such as CD8 T cells, NK cells, and γδ T cells kill tumor cells. Helper cells, including Th1 promote antitumor immunity. In contrast, suppressor cells such as MDSCs and Tregs suppress antitumor immunity. Phagocytes such as macrophages and neutrophils phagocytose tumor cells or tumor cell debris. MDSC, myeloid-derived suppressor cells; NK, natural killer; Th1, T helper 1; Tregs, regulatory T cells.

Fig. 3. Role of hypoxia in antitumor immunity. Oxygen tension decreases close to the tumor core. Under normoxia, antitumor immunity occurs normally. Under hypoxia, oxygen deprivation induces tumor cell invasion, radioresistance, and necrosis. Immune cells also undergo hypoxia. The metabolic fitness of immune cells is disrupted. Immunosuppression resulting from M2 macrophage polarization and T cell exhaustion is mediated by hypoxia.