Prof. Yardena Samuels' lab at the Weizmann Institute of Science has succeeded in making cancer cells surrender themselves to the immune system. The new approach may offer hope to incurable patients
When a social network profile starts posting strange or threatening statuses, it can be concluded that it has been hacked and disabled. Cells in the body also update their "status" - they present to their environment short proteins that are produced in the cell at all times. The immune system monitors these statuses and destroys cells that display strange proteins. A classic example of this is a cell infected with a virus, displaying parts of the viral proteins on its surface - and thus the immune system cells recognize and eliminate it. Cancer cells, on the other hand, sometimes manage to stay under the radar and only display suspicious proteins that could be targets for identification and attack by the immune system. A new approach to cancer treatment developed by scientists from Prof. Jordana Samuels The Weizmann Institute of Science is expanding the bank of targets for fighting cancer by disrupting the protein production process in malignant cells. In an article published today in the scientific journal Cancer Cell The scientists show that the disruption causes cancer cells to incriminate themselves – they begin to display dozens of suspicious proteins and lead to a powerful immune response that can eliminate human cancer cells and inhibit the development of aggressive tumors in a mouse model.
Immunotherapy, the new generation of cancer treatments, is based on recruiting the patient's immune system to fight the tumor. Although it is a revolution in the field of cancer medicine, these treatments still help only a minority of patients. In order for the immune system cells responsible for identifying suspicious cells – killer T cells – to be able to effectively eliminate the cancerous tumor, they must first be able to identify the cancer cell as a foreign agent that must be destroyed. This can happen due to mutations in the recipes for protein production that lead to the presentation of strange proteins, but in many types of cancer there are a few mutations – and therefore there is a lack of effective targets for identifying and attacking the cancer cells. "Damaged proteins do not have to result from an error in the 'recipe' in the DNA, i.e. a mutation, they can also be created due to a failure in the production stage itself – i.e. the 'translation' process," explains Prof. Samuels. "In the new study, we decided to test whether we could increase the bank of targets for identifying and attacking cancer cells by deliberately disrupting this process."
During the translation process, the ribosome, the cell's protein-making factory, reads the genetic recipe and assembles the protein from its building blocks – amino acids. The recipe itself is a long sequence of RNA bases that serve as "letters," with every three letters representing a "word" that dictates which amino acid should be inserted into the protein chain. Because this is a sensitive and vital process, there are many enzymes in the cell that are responsible for ensuring that the ribosome reads the genetic recipe accurately without accidentally skipping a single letter forward or backward. To disrupt translation in human melanoma cancer cells, the team of researchers, led by Chen Weller and Dr. Osnat Bartok from the lab of Prof. Samuels and Dr. Christopher McGinnis at Stanford University, used genetic engineering methods to delete one of these enzymes. The deletion caused the ribosome to skip its reading, lose the correct division into words, and insert the wrong amino acids into the protein. The scientists were able to identify 34 short proteins whose production is unique to the cancer cells disrupted in the study and showed that some of them could be effective and novel targets for activating an immune response to cancer.
Next, the scientists tested in a mouse model whether disrupting translation in melanoma tumors that do not elicit an effective immune response actually leads to its activation. They observed that when they disrupted translation and caused the cancer cells to produce strange proteins, the population of killer T cells that were activated against the tumor and infiltrated its environment increased even more. However, when the T cells reached the tumor environment, they lost their killing ability and became “exhausted” – a well-known and recognized problem in the field of cancer medicine.
Some of today's leading immunotherapies were designed to tackle this very problem, blocking the debilitating signals that cancer sends to T cells. The scientists hypothesized that if they combined existing treatments with their new approach, they would be able to better fight tumors. "The existing immunotherapy, which was not at all effective in the type of melanoma we were testing, suddenly became very effective when given to mice after disrupting translation in their cancer cells," says Prof. Samuels. "The combination treatment was able to eliminate or greatly reduce the tumor in 40% of the mice."
A new measure of immunotherapy success
The new findings could translate into groundbreaking cancer treatments in the future, but they may also have more immediate implications. Currently, it is customary to offer immunotherapy treatments to patients with cancer tumors with multiple mutations, but there are also cancer patients who are not candidates for immunotherapy due to the small number of mutations, even though their tumors may have a decrease in the expression of the enzyme that maintains the reliability of translation. As part of the study, the scientists showed that a low level of this enzyme is another factor that can predict the success of immunotherapy treatments. "Finding a new predictive index for the effectiveness of immunotherapy treatments will make it possible to offer them to patients who have so far been avoided," explains Prof. Samuels.
Beyond clinical developments of one kind or another, the study presents a completely new approach to cancer treatment. "This is proof of the feasibility of deliberately damaging the translation machinery leading to an increased immune response against cancer cells," says Prof. Samuels. "There are more than 600 different factors involved in the translation process of proteins, and they could be future targets for developing treatments. We are already looking, in collaboration with Stanford University and using artificial intelligence tools, for additional targets for disrupting translation in cancer cells. Also, since the translation process does not vary from one cell type to another, a treatment that can disrupt it in a targeted manner in one type of cancer cell could be effective in many types of cancer. We are already examining the disruption of translation in breast cancer, colon cancer and pancreatic cancer."
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