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By Aris Krikelis, PhD
Hypoxia is a common feature of the tumor microenvironment and occur in a multitude of cancers. It reduces tumor immunogenicity by attenuating cytotoxic T cell function and attracting regulatory T cells.
The hypoxic tumor microenvironment is caused by increased oxygen consumption due to hyperplasia and decreased oxygen delivery due to increased diffusion. The hypoxic response is primarily driven by the hypoxia inducible transcription factors (HIFs). Under normoxic conditions HIFs are continuously degraded following hydroxylation of proline residues by prolyl hydroxylase domain (PHD) proteins. Hydroxylation of HIF1 allows the von Hippel-Lindau E3 ubiquitin ligase to ubiquitinate HIF1 resulting in the latter's proteasomal degradation.
Under hypoxia, reduced O2 levels are rate limiting thus decreasing levels of PHD-mediated proline hydroxylation of HIF1. This results in the increase of HIF1 protein levels. HIF-mediated pathways influence metabolic adaptation through mTOR signaling, erythropoiesis, angiogenesis, cell growth, vascular tone and differentiation. Many genes that are regulated by HIF1α are expressed at increased levels in cancer cells, particularly angiogenic growth factors (VEGF) and enzymes that regulate glucose metabolism. Activation of HIF commonly occurs in tumors and can be an indicator of poor prognosis. Increased HIF1α activation positively correlates with aggressive phenotypes.
More than forty years ago, Hellström and colleagues noticed that tumors and cytotoxic T cells coexist in cancer patients. Tumor hypoxia is a key factor in the dampening of cytotoxic T cell activity, which manifests itself as resistance to perforin and granzyme B, as well as reduced T cell production of IFN-γ among others. The main mechanisms of hypoxia-induced anti-tumor T cell suppression are:
In addition, tumor-produced VEGF binds and activates VEGF receptor 2 which in turn phosphorylates STAT3. Phospho-STAT3 increases cancer cell resistance to T cell cytotoxicity, in an as-yet unclear mechanism that does however seem to involve the Akt pathway.
Regulatory T cells (Treg), also known as suppressor T cells, are well known as mediators of anti-tumor immune suppression. Tumors chemotactically attract Treg cells through secretion of SDF1 which binds CXCR4 receptors on the Treg cell surface. Once at the tumor microenvironment, the hypoxic conditions trigger HIF1-dependent upregulation of FOXP3 expression, which in turn leads to increased IL-10 secretion. The latter is an anti-inflammatory cytokine that suppresses the antigen-presenting ability of dendritic cells and inhibits synthesis of pro-inflammatory cytokines.