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 entirely different meanings. “Maybe this is a mechanism cancer cells use to survive against all odds,” says Agami. “But we don’t have any proof for that yet.”
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.
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.
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.