A hypoxic environment is a common characteristic of tumors for many cancers. The lower level of oxygen reduces the immune response surrounding the tumor (immunogenicity) by attracting regulatory T cells and reducing the ability of other T cells.
The hypoxic microenvironment that is characteristic of many tumors is the combined result of a reduced amount of oxygen delivery, due to greater diffusion, and an increase in oxygen consumption due to the rapid growth (hyperplasia) of the tumor.
The Hypoxic Response
The hypoxic response is a biochemical process that occurs in hypoxic environments. The response is encouraged by HIFs - hypoxia inducible transcription factors.
Under normal oxygen (normoxic) conditions the hypoxic response does not occur as HIFs undergo constant breakdown via the hydroxylation of proline residues by PHD (prolyl hydroxylase domain) proteins. The hydroxylation of HIF1 proline residues opens HIF1 to ubiquitination by the von Hippel-Lindau E3 ubiquitin ligase, which results in HIF1’s breakdown.
In hypoxic conditions the reduced levels of oxygen limit the rate of HIF1’s proline hydroxylation resulting in higher cellular HIF1 levels. HIF regulates pathways which impact metabolic adaption through cell growth, angiogenesis, erythropoiesis, mTOR signaling and vascular tone.
Due to the hypoxic conditions of cancer cells, genes that are regulated by HIF1α show greater levels of expression. In particular, genes relating to glucose metabolism regulation and angiogenic growth factors (VEGF) are expressed to a greater extent. Activation of HIF occurs frequently in tumors and when identified medically it can indicate the progression of the disease, i.e. a poor disease prognosis. Greater levels of HIF1α has been shown to correlate with aggressive cancer phenotypes.
Hypoxia and Reduced T Cell Cytotoxicity
Over forty years ago research conducted by Hellström et al. found that tumors and cytotoxic T cells can coexist, with the tumors experiencing less cytotoxicity than expected. It was found that the hypoxic microenvironment created by tumors results in a reduced cytotoxicity of the T cells. This reduced cytotoxicity can be observed as resistance to granzyme B and perforin, and a lower rate of IFN-γ production by T cells.
The key mechanisms by which T cell cytotoxicity is reduced in hypoxic environments are:
- Increased expression of arginase (argI) and inducible nitric oxide synthase (iNOS) as a result of increased HIF1α levels. The increased levels of argI and iNOS negatively impact T cell cytotoxicity.
- COX2 upregulation, which results in the increased conversion of arachidonic acid into prostaglandin PGE2. PGE2 interacts with myeloid-derived suppressor cells, via EP4 receptors, to make them more immunosuppressive. PGE2 is also thought to downregulate the production of IL-12 and to prevent the development of dendritic cells.
- An increase in the extracellular concentration of cyclic AMP. Cyclic AMP binds to T cell surfaces via A2A receptors.
In addition to the above mechanisms tumors also produce VEGF, a compound which binds to the VEGF receptor 2. VEGF receptor 2 then phosphorylates STAT3, which has been shown to make cancer cells less vulnerable to the cytotoxicity of T cells. This process is not as well understood but appears to follow the Akt pathway.
The Role of Treg Cells in Immune Suppression
Regulatory T cells (Tregs), sometimes called suppressor T cells, have established roles in the mediation of anti-tumor immune suppression.
Tumors have been shown to attract Treg cells using a chemotactical method which involves the secretion of SDF1, which then attaches to receptors on the surface of the Treg cell. Once Treg cells are exposed to the hypoxic environment surrounding the tumor FOXP3 expression is upregulated via a HIF1 driven mechanism. The increased levels of FOXP3 result in more IL-10 secretion.
IL-10 is a cytokine that shows anti-inflammatory behavior, which reduces the production of pro-inflammatory cytokines and reduces the ability of dendritic cells to show antigens.
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