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​New Hope to Combat Tumor Activity with Increased T-Cell Survival

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Diane Lee
Edited by Chris Lew
December 30 2016
Current Research
T-cells play an important role in the immune system because they carry out a multitude of immune responses by recognizing virus-infected cells and attacking them directly. Once they are done with their job, T-cells self-destruct, but some are able to survive as memory T-cells. Memory T-cells induce long-term protection as they have “memory” of fighting against previously encountered pathogens. Metabolic activity is a factor in determining a T-cell’s fate.

​Mitochondrial fatty acid oxidation is needed to generate memory T-cells. The mammalian target of rapamycin (mTOR) is the main regulator of cell metabolism and controls T-cell memory formation. Healthy metabolism and T-cell survival are needed to ensure the prevalence of anti-tumor responses. In a tumor microenvironment, T-cell dysfunction, stress, and cell death are frequent because of the scarce nutrients in the environment.

L-arginine levels affect T-cells in different ways. Increased intracellular L-arginine levels improves T-cell survival. It induces metabolic changes, which include decreasing glycolytic activity and increasing oxidative phosphorylation activity in activated T-cells. This activity may enhance memory T-cell formation and anti-tumor responses. However, L-arginine treated T-cells cause a delay in cell proliferation. T-cells can sense L-arginine depletion, which can occur in tumor microenvironments. A moderate reduction of L-arginine has a negative impact on T-cell survival without affecting proliferation. When L-arginine was completely depleted from the culture medium, T-cells no longer proliferated. Lack of L-arginine in T-cells can be sensed by GCN2, leading to an amino acid starvation response; it can also be sensed by SLC38A9, leading to the inhibition of T-cell growth and proliferation.
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This is a general schematic of how a cytotoxic T-cell targets and removes infected or cancerous cells.
Image Source: "T cytotoxic interaction with infected cell" by Becky Boone is licensed under CC BY-SA 2.0
L-arginine also has other beneficial effects. For example, there was an increase in number and activity of natural killer cells in healthy volunteers who took L-arginine orally. L-arginine also improves mitochondrial function and reduces bronchial epithelial cell deaths after an allergic airway inflammation. It also has a beneficial effect for the treatment of patients with a mitochondrial disorder.

Three nuclear proteins (BAZ1B, PSIP1, and TSN) are crucial in T-cells for L-arginine to have an effect on T-cell survival. BAZ1B is a transcriptional regulator that binds to methylated histones. PSIP1 is a transcriptional co-activator that protects a cell from self-destruction. L-arginine causes structural changes in BAZ1B and PSIP1, which may affect DNA binding and lead to the initiation of T-cell survival. The last nuclear protein, TSN, is a small DNA and RNA binding protein that can influence cellular phenotypes. These three proteins had variable responses to L-arginine. This finding further confirms that L-arginine can be sensed by several independent proteins and can lead to increased T-cell survival.
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In the future, this finding may offer the possibility of therapeutic applications. Genetic manipulations are no longer needed to cause a change in metabolite levels. The positive relationship between increased levels of L-arginine and T-cell survival may be exploited therapeutically. Lastly, it may lead to future studies of the complex relationship between metabolism and cellular functions. 
​Featured Image Source: "Killer T cells surround a cancer cell" by NICHD is licensed under CC BY-NC-ND 2.0

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