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TORONTO — Researchers have discovered the closest thing to cancer’s off switch: a specific protein part with the ability to trigger cancer cell death.
A team at the University of California, Davis Comprehensive Cancer Center has identified an epitope on the CD95 cell receptor that can start a chain reaction that essentially tells the cell to self-destruct. Researchers believe this epitope could be exploited in new treatments to halt the progression of cancer cells. their footprints.
Scientists have long known that the CD95 receptor, known as Fas, is key to killing cells. This is often called the “death receptor.”
But researchers say so far they haven’t been able to do much with that knowledge. Their findings are described in a paper published in a peer-reviewed journal earlier this month. Nature journal “Cell Death and Differentiation”.
“We have discovered the most important epitope for cytotoxic Fas signaling as well as bystander anti-tumor function of CAR T cells,” said the study’s senior author and director of the Department of Medical Microbiology and Immunology. said Associate Professor Jogender Tushir-Singh. at the University of California, Davis School of Health and Medicine, said in a press release.
“Previous efforts to target this receptor have been unsuccessful, but the identification of this epitope may open the door to therapeutic targeting of Fas in tumors.”
An epitope is a group of amino acids or chemicals, usually part of a protein, located on the surface of a molecule that is recognized by the body’s immune system, specifically antibodies, B-cell receptors, or T-cell receptors. will be done. When a particular immune cell interacts with the appropriate epitope, it is similar to lighting the fuse of an explosive, activating the protein and, in the case of this key epitope on Fas, leading to cell death.
The researchers believe they can begin to develop antibodies that selectively use this newly identified epitope to bind to and activate Fas on cancer cells in solid tumors, causing cell death.
The researchers also believe this study may identify ways to make current treatments more efficient, targeting other areas of cancer while causing cancer cell death as a side effect. .
Complications of cancer treatment
There are many treatments to fight cancer, but when cancer returns despite surgery, chemotherapy, and radiation therapy, doctors often try immunotherapy. Immunotherapy is a therapy that strengthens the immune system to help the body destroy cancer.
One example is CAR T cell-based immunotherapy, in which researchers edit a patient’s T cells by implanting specific tumor-targeting antibodies into them and inducing them to attack tumor cells.
Although this treatment has shown promise in the fight against leukemia and other blood cancers, it has not been widely used in solid cancers such as ovarian, breast, and lung cancers because the environment is quite different. I didn’t.
“These are often referred to as cold tumors because immune cells are unable to enter the microenvironment and exert a therapeutic effect,” said Professor Tushir Singh. “If the antibodies and T cells that activate immune receptors can’t get to the tumor cells, it doesn’t matter how well we manipulate them. So we need to create space for the T cells to infiltrate. .”
The death receptor Fas may be the gateway to solid tumors that researchers have been searching for. Drugs that promote death receptor activation may not only kill more cancer cells, but also create the openings needed to deliver more therapeutic agents into the tumor itself.
And the identification of this important epitope may just open the door.
“Bystander effect”
Researchers are now able to develop antibodies that target this epitope to cause cancer cell death, as well as learn more about how to identify the presence of this epitope in patients’ cells and leverage CAR T-cell immunotherapy. I hope that I can provide you with good ideas. .
Agents that target this specific epitope may cause a “bystander effect” when used in combination with CAR T-cell immunotherapy, even though CAR T-cell therapy lacks the molecules it is designed to destroy. Cancer cells may be eliminated by drugs. Target this newly identified epitope.
In previous studies, the bystander effect did not work because receptors that inhibit cell death were better at binding to therapies that sought to target Fas. Targeting antibodies against this epitope could change the game.
The study also found that patients with a mutated version of this particular epitope on the Fas receptor had no response to CAR T cell immunotherapy, suggesting that this epitope also serves as a biomarker for the efficacy of this existing therapy. It was suggested that there is a possibility. .
“Before we consider administering CAR T, we need to know the patient’s Fas status, especially the mutations around the epitope discovered,” Tushir-Singh said. “This is a definitive marker of bystander therapeutic efficacy of CAR T therapy. But most importantly, it activates Fas and selectively kills tumor cells, allowing CAR T cell therapy in solid tumors to This will set the stage for developing antibodies that potentially support this.”
So far, no antibodies developed to target Fas have reached clinical trials. Researchers hope that with this new knowledge about how to optimally activate these death receptors, they may soon start seeing that change.
