Metabolic-checkpoint combined approach of the inhibitor may improve cancer therapies -
Reprogramming normal metabolism underlying molecular pathways is essential for the function of T cells fight against infection and the immune system to form a "memory" of microbes that already met. But exactly how the metabolism in T cells remained depleted in chronic infections and cancer is a missing element in this line of research. Now, a new study suggests that tweaking metabolic steps in combination with checkpoint blockade medications can improve certain cancer treatments, according to a new study from the School of Medicine Perelman University of Pennsylvania. The team published their results this week in immunity.
When T cells are activated due to a microbe or a tumor in a host, "they have a lot of work to do. They need to make many copies of themselves in generating building blocks to manufacture new cells, "said lead author E. John Wherry, PhD, director of the Institute of immunology, Microbiology professor and co-director of the Institute for cancer Parker Penn immunotherapy. "T cells must radically change their energetic lifestyles, ranging from sedentary couch potato existence to be a marathoner in a very short time."
Physiologically, this transformation involves going from one existence "catabolic" slow metabolism to burn to "anabolic" one in which the body starts to produce chemical intermediates to build new cells. But the T cells are wired to stop the rapid anabolic pathway mode after a certain time because the operation at this level is unsustainable.
"We found that, in the first week of a chronic viral infection, even before severe dysfunction of T cells is established, the virus specific T cells are already unable to meet the demands of bioenergy T cells generated during the height of the fight against viral infection although contained in a mouse model, "said Wherry.
PD-1, a cell surface receptor and the target of anticancer drugs currently used, indicating the T cells to turn off the anabolic pathway, but other molecular signals say keep this pathway activated because infection chronic or to growing tumors are still present. "Now we have cell metabolically confused T," says Wherry.
Many tumors produce proteins that bind to PD-1 to stop the T cell signal, and drugs that block this process is one of the most prolific areas of cancer research.
infection of the team induced in mice using two different strains of lymphocytic choriomeningitis virus (LCMV), a well-studied model system for exploring the biology of T cells in a group of mice, the virus has been cleared in a week by healthy cells or effector T and another group, the game has derailed T cells become exhausted. effector T cells allow a greater amount of anti-tumor cytokine or anti-microbial and do accelerating cell replication. . exhausted T cells, on the other hand, as their name suggests, have lost this ability
The study identified the time - earlier than previously thought - when PD-1 disables signal anabolic metabolism. This discovery has implications for the clinic, because it identifies the altered metabolism as a separate item in the development of T cell depleted from the following later exhausted T cells.
These results also identify PD-1's role in the metabolic switch off anabolic pathways and characterize the metabolic regulation of downstream targets PD-1. For example, the restriction of glucose uptake and use (required for production of new cells), despite the upregulation of multiple metabolic pathways backup, is a metabolic disorder of the exhausted T cells. PD-1 partially control the development of this defect at the beginning of the use of glucose as a fuel, and the size and quality of the mitochondrion, the powerhouse of the cell.
A second route suppressed by PD-1 involved PGC-1 , a protein that regulates genes involved in metabolism. Correcting this defect PD-1 induced PGC-1α enhanced overexpression bioenergy exhausted T cells
One area on the horizon of research, Wherry says, is to find a way to improve T cells depleted by testing drugs that manipulate metabolism such as activators of PGC-1 or related pathways that could be targeted by drugs such as metformin or resveratrol. The team will also explore ways to improve the health of pharmacologically mitochondria.
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