Cancers like melanoma are very sneaky, evading or fighting treatments when they can – and thus often exceedingly difficult to treat. Joint research effort by scientists at the Weizmann Institute of Science in Rehovot and researchers in the Netherlands Cancer Institute in Amsterdam and the University of Oslo in Norway reveals exactly how tumors, in their battles to survive, will go so far as to starve themselves to keep the immune cells that would eradicate them from functioning.

The immunotherapies currently given to melanoma patients work by removing obstacles that keep immune cells called T cells from identifying and killing tumor cells. Recent research suggested that in melanoma, another blocker could assist the T cells – this one to stop an enzyme called IDO1 that is overproduced by the cancer cells. I

DO1 breaks down an essential amino acid called tryptophan, which is needed to make proteins, and in the process, it leaves behind tryptophan breakdown byproducts that suppress the immune response. But IDO1 blockers did not succeed clinical trials, suggesting more knowledge was needed, including how the cancer cells, which also require tryptophan, can function after they have destroyed this resource. 

The research team, including the group of Prof. Yardena Samuels of Weizmann’s molecular cell biology department including Dr. Noam Stern-Ginossar, members of the lab of Prof. Reuven Agami of the Netherlands Cancer Institute; Dr. Yishai Levin and his group at the Nancy and Stephen Grand Israel National Center for Personalized Medicine on the Rehovot campus; and the group of Prof. Johanna Olweus of the University of Oslo, investigated the mystery of the missing tryptophan in melanoma cells. 

Agami and his team had, in previous research, shown that in normal cells, when an amino acid like tryptophan is missing, a sort of logjam is created in the protein production process. The ribosomes – protein production units – make their way down a strand of messenger RNA (mRNA), translating three-letter “words” known as codons into amino acids, which they grab and add to the expanding protein chain. When an amino acid is missing, the ribosomes stop working until one can be found, causing a pile-up in the ribosomes coming up the mRNA strand from behind. 

But that is not what happens in melanoma cells. The researchers found that some ribosomes manage to keep going, past the codons encoding the missing tryptophan. 

It turned out that the melanoma ribosomes were engaging in a wayward scheme known as “frameshifting” – they simply moved up or down one letter in the RNA strand. In the economical gene code – based on just four letters – the next three spelled the name of a different amino acid and the ribosomes continued down the mRNA strand, assembling protein chains. Of course, the frames of subsequent codon triplets shifted as well, so that the resultant proteins were quite abnormal. The cancer cells then displayed them on their outer membranes, where immune cells could pick up on the aberrant protein structures. 

Such frameshifting had been seen before in viruses and bacteria, but never in human cells. Previous studies have missed these proteins because they don’t come from genetic mutations (of which there are hundreds in melanoma) but from a sort of calculated blip in the production process. Agami, whose lab is now investigating exactly how this frameshifting is initiated and whether it occurs in other cancers, explained: “This flexibility in mRNA translation might stimulate tumor growth and aggressive behavior by using an emergency program for scarcity.” 

Dr. Osnat Bartok, who works in Samuels’s group, added: “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.” 

Samuels concluded that “these findings add to our knowledge of immune system interactions with cancer as well as the landscape immune cells encounter in a tumor. They suggest exciting ways we might regulate and therapeutically target the presentation of defective immune-reactive peptides on the cell surface.”