9 March 2022

Tumor cell produces faulty proteins, even without DNA errors

A new discovery could lead to immunotherapy that turns “cold tumors” into “hot tumors”.

Elize Brolsma

Elize Brolsma

Elize is part of Oncode’s communication team. She has over 10 years of experience in the com-munication industry, both for commercial and non-profit organisations. After obtaining her bache-lor and master degree in communication at Utrecht University, Elize worked as a communication professional at a research institute, PR agency, law firm and internet company. She has a strong focus on external communications and Public Relations. At Oncode - together with her colleagues - Elize produces the monthly newsletters for Oncode Investigators & Researchers and the Oncode digital magazine. She publishes content for the Oncode website and is responsible for all social media channels. She enjoys discussing science with researchers and support them in their outreach.

Tumor cells produce proteins with tiny changes, even without prior changes in their DNA code: a phenomenon that has never been shown before and that is specifically seen in tumors. These proteins are different from their normal counterparts so that they can activate the human immune system. And that could provide us with new leads for new types of immunotherapy against cancer, in which “cold” tumors are made “hot.”

This is the latest discovery by Oncode Investigator Reuven Agami’s research group at the Netherlands Cancer Institute. First authors Abhijeet Pataskar, Julien Champagne, Remco Nagel, Agami himself, and others, published their findings in Nature on March 9, 2022. Nature also dedicated a 'News & Views' section to this research.

“This is the first time that someone has shown that a protein is specifically changed without being preceded by changes in the DNA,” says Agami. “This has never been shown in mammals, but it has been observed in bacteria.”

New finding, new terminology: substitutant
The investigators even had to come up with a new word for these new, strange proteins that they observed as a single red dot on their PC screen. They named them substitutants: a hybrid of the words substitution and mutant. Substitution is the exchange of a protein’s building block (amino acid), while a mutation is a change in the DNA. Research leader Agami: “The editors of the journal Nature first had to examine whether this word didn’t already exist, and if not, whether our newly coined term had the right meaning.”

Shortage of nutrients in cancer cell
Normally, proteins are synthesized by translating the DNA code into a string of building blocks (amino acids). Substitutants develop when a cancer cell lacks the building block tryptophan (in biology often abbreviated with the letter W). This is a nutrient that the body cannot produce, but which is required to stay alive.

From Always to Alfays
The enzyme that normally recognizes tryptophan, now recognizes a different amino acid, phenylalanine (shortened to the letter F). This leads to the inclusion of an erroneous building block in the proteins, replacing the W with an F. Just to give an example, without tryptophan, the word “Always” is erroneously formed, leading to “Alfays” instead. The two may sound similar, but have an entirely different meaning. “Maybe this is a mechanism cancer cells use to survive against all odds,” says Agami. “But we don’t have proof for that yet.”

Substitutants change “cold tumors” into “hot tumors”.
This is a fascinating problem, but what truly intrigues Agami is finding out what we can do with these substitutants. These new proteins are so unnatural that they can easily be recognized by the T cells found in our immune system.

And that’s very beneficial, because this phenomenon also occurs in tumors that are naturally not very sensitive to immunotherapy because they have few mutations in their DNA – such as pancreatic, prostate, and brain tumors, as well as the majority of colorectal cancers. These are often considered “cold tumors”. Tumors that show a significant number of DNA mutations (hot tumors) like melanoma or lung cancer are more easily spotted by the immune system during immunotherapy treatment.

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Organoids from colorectal cancer
Substitutants can turn these “cold tumors” into “hot tumors”, the researchers now know. They witnessed this effect right in front of their eyes in organoids (tumors grown in the lab) of a type of colorectal cancer that barely responds to immunotherapy.

Agami: “We noticed that these tumor cells did not produce many tumor-specific protein pieces that can be recognized by the immune system at first. But once we induced the formation of substitutants in the lab by removing the nutrient tryptophan, we suddenly observed plenty!” The investigators also discovered great numbers of substitutants in hundreds of tumors from patients across more than six different cancer types.

New type of cell therapy
The researchers now want to develop a new type of cell therapy in which they remove T cells from the blood of healthy people, and clone the receptor that is vital to the recognition of the substitutants. They have already found such a receptor in the cancer type glioblastoma (a malignant brain tumor). This receptor can be placed back in the T cells – instructing them to destroy tumors that produce substitutants. This new therapy is intended to be an addition to immunotherapy with checkpoint inhibitors, especially for patients with “cold tumors”.

This isn’t the first time that Reuven Agami’s group discovered that cancer cells produce aberrant proteins when there aren’t enough building blocks available for protein synthesis. They previously showed that tumor cells can create aberrant proteins by slipping up during their production when essential nutrients are not available. Together with their discovery of the substitutants, this cancer-specific sloppiness gives us new tools to arm the human immune system against “cold tumors”.

This research was conducted at the Netherlands Cancer Institute with contributions from the research groups of Johanna Olweus (Oslo University, Norway) and Michal Bassani Sternberg (Ludwig Institute for Cancer Research, Switzerland).

It was funded by the Dutch Cancer Society, the European Research Council, and the Antoni van Leeuwenhoek Foundation, and supported by the Oncode valorization team Amber Liu and Emil Pot who assisted in the patent filing process and the development of a dedicated Oncode program.

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