Cancers hurt, starve themselves to trick immune system, new study finds
To avoid the immune system, melanoma breaks down the amino acid tryptophan, stopping cells from properly functioning, but the cancer cells are able to do so despite lacking tryptophan themselves.
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In their efforts to survive and keep the immune system at bay, cancers in the human body have been observed to starve themselves in order to stop immune cells from functioning, according to a new study from the Weizmann Institute of Technology.
Oncologists for decades have struggled with finding new methods for combating the progression of cancer, but many strains like the skin cancer melanoma are particularly difficult, as they have several means of keeping the immune system at bay.
While existing immunotherapies for the cancer work by removing obstacles that keep T cells, a type of immune cell that identify and remember threats as well as eliminate them, from finding and killing tumors. However, melanoma often persists, and overcame trials for a blocker for IDO1 (an enzyme released by cancer cells to suppress the immune system by breaking down an essential amino acid called tryptophan), suggesting more research was needed into understanding how the cells work.
But the research team including the group of Prof. Yardena Samuels of Weizmann’s Molecular Cell Biology Department, members of the lab of Prof. Reuven Agami of the Netherlands Cancer Institute; Dr. Noam Stern-Ginossar of the Weizmann Institute’s Molecular Genetics Department; Dr. Yishai Levin and his group at the Nancy and Stephen Grand Israel National Center for Personalized Medicine on the Institute campus; and the group of Prof. Johanna Olweus of the University of Oslo – investigated, and observed a strange quirk of melanoma cells that differ them from normal cells.
In normal cells, when tryptophan is missing, the protein-making process gets stuck, with ribosomes who help with the process stopping to work and piling up in the mRNA. Essentially, the cells stop working properly. But confusingly, in breaking down tryptophan, the cancer cells themselves are being deprived of the same amino acid. And yet, they still function without it, with the ribosomes still managing to go through.
And now, scientists have solved the mystery. It was discovered that melanoma ribosomes do what is known as "frameshifting," moving up or down the RNA strand and essentially disguising as a different amino acid. The result of this shifting means that the proteins subsequently developed were abnormal.
This is a process observed before, but only in bacteria and viruses. Because they do not arise from genetic mutations, but instead more of a calculated and intentional glitching of the process, studies had previously missed observing this process.
“When things get stressful in the tumor’s microenvironment, it can affect protein production, harming immune cells but also adding to the immune cells’ clues for identifying cancer,” Dr. Osnat Bartok, one of the researchers in Samuels' group, said in a statement.
It remains unclear if this is a feature exclusive to melanoma, and Agami's lab is now investigating if it manifests in other cancers.
But in addition to solving a mystery in the functions of melanoma, it can also pave the way to major breakthroughs in cancer treatment.
“These findings add to our knowledge of immune system interactions with cancer as well as the landscape immune cells encounter in a tumor," Samuels explained.
"They suggest exciting ways we might regulate and therapeutically target the presentation of defective immune-reactive peptides on the cell surface.”
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