Why do T-killers get tired?
Cells tired in the fight against cancer were cheered up with pyruvate
Vera Mukhina, N+1
The latest issue of Science Immunology published an article investigating the causes of fatigue T-killers in the fight against cancer (Gemta et al., Imposed enolase 1 glycolytic activity restricts effector functions of tumor-infiltrating CD8+ T cells). Consistently rejecting all incorrect hypotheses, a group of American researchers came to the conclusion that insufficient activity of enolase, an enzyme included in the glycolysis pathway, is to blame for this. Having eliminated the cause of fatigue, the scientists managed to restore the activity necessary for the cells to defeat the tumor.
The immune system actively prevents the occurrence of different types of cancer and often the outcome of the disease depends on the intensity of its actions. Cancer cells, in turn, try their best to reduce its activity and secrete substances that exhaust cancer-specific T-killers fighting them: the latter stop releasing toxins in sufficient quantities, actively divide, and their presence becomes less effective. Recent studies have shown that this is due to a violation of glucose metabolism, but the mechanism of this effect is not fully understood. In conditions of limited resources, immune cells and cancer cells compete for glucose, and somehow the latter have learned to influence the glucose metabolism of lymphocytes.
To unravel what exactly they affect, Lelisa Gemta from the University of Virginia and her colleagues compared the glucose metabolism of T-killers battling melanoma mice with control naive and active T-cells of mice without a tumor. It turned out that in the cancer-specific T-killers selected from mice, glucose uptake is not similar to any of the control examples: it goes worse than in active lymphocytes, but more intense than in naive cells, which are generally characterized by a lower metabolic rate.
In the next step, the researchers decided to test why glucose oxidation is not as effective as in conventional active T cells. The analysis showed that glucose transporters in cancer-specific T-killers are in perfect order, which means that the version about glucose deficiency can be excluded. Thus, the researchers concluded that perhaps the key to solving the fatigue of lymphocytes lies in the very pathway of glucose oxidation. After checking the concentrations of metabolites of this pathway, the authors of the article found a tenfold decrease in the level of phosphoenolpyruvate and subsequent metabolites in the pathway compared with the control.
The difference between cancer-specific (right) and control active T cells (left) is in the amount of phosphoenolpyruvate, RNA enolase and the enzyme itself. Drawings from an article in Science Immunology.
The catalysis of the synthesis of phosphoenolpyruvate from its precursor is carried out by the enzyme enolase 1. Testing of this enzyme gave unexpected results: the gene encoding this enzyme was actively expressed, and the protein itself was also presented in abundance. This meant that the activity of this enzyme was somehow limited at the post-translational level, that is, after protein synthesis. Testing of its enzymatic activity showed that it is reduced and does not increase in response to stimulation of T-killers.
Having understood the cause of fatigue of cancer-specific T-cells, the researchers suggested a way to help them. First, they tried to bypass the blockade of the metabolic pathway by feeding the cell with pyruvate, the end product of glycolysis. This worked, and returned the fatigued cells to enzymatic activity.
As an alternative, they tried to act on PD-1 – a protein known as a glycolysis blocker for other cancers – and thus unblock the non-functioning enolase. Treatment of cancer with specific checkpoint inhibitor antibodies (including PD–1 antibodies) gave a positive result and restrained tumor growth. Apparently, multiple exposure to checkpoint inhibitors is needed to restore enolase activity, because treatment with them separately did not give positive results.
A is the total number of T–killers per square millimeter of the tumor using checkpoint inhibitors (right) and without it (left). B,C – dynamics of tumor growth in both cases.
Having received such results, the researchers decided to test how applicable they are to humans. Taking tumor samples from donors, they showed that in cancer-specific T cells, as in mice, the activity of enolase is reduced, so perhaps this problem can also be corrected by checkpoint inhibition.
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