Researchers find a Cancer Cell Death ‘Switch’

Researchers find a Cancer Cell Death ‘Switch’

A UC Davis Comprehensive Cancer Center research team discovered a critical epitope (a protein portion that can activate the bigger protein) on the CD95 receptor that can cause cancer cells to die. This new ability to induce programmed cell death could pave the way for better cancer treatments. The findings were published in the journal Cell Death & Differentiation on October 14th.

Death receptors are CD95 receptors, commonly known as Fas. Protein receptors are found on cell membranes. When activated, they send out a signal that causes the cancer cells to die.

Modulating Fas may also expand the benefits of CAR T-cell treatment to solid malignancies such as ovarian cancer.

“We discovered the most critical epitope for cytotoxic Fas signaling as well as CAR T-cell bystander anti-tumor function,” said senior author Jogender Tushir-Singh, an associate professor in the Department of Medical Microbiology and Immunology.

“Previous attempts to target this receptor were unsuccessful.” But now that we’ve found this epitope, there may be a way to target Fas in cancers,” Tushir-Singh added.

Finding more effective cancer treatments
Surgery, chemotherapy, and radiotherapy are commonly used to treat cancer. These treatments may be effective at first, but therapy-resistant tumors frequently reoccur. Immunotherapies such as CAR T-cell immunotherapies and immunological checkpoint receptor molecule activating antibodies have showed great potential in breaking this loop. However, they only benefit a very small number of patients, particularly those with solid tumors such as ovarian, triple-negative breast cancer, lung, and pancreas cancer.

T cells are an immunological cell type. CAR T-cell therapies involve modifying patient T cells to fight cancers by grafting them with a specific tumor-targeting antibody. These modified T cells have proven efficacy in leukemia and other blood malignancies, but have failed to deliver results against solid tumors on multiple occasions. The explanation for this is because tumor microenvironments are effective at suppressing T cells and other immune cells.

“These are often called cold tumors because immune cells simply cannot penetrate the microenvironments to provide a therapeutic effect,” she said. “It makes no difference how well we engineer immune receptor activating antibodies and T cells if they can’t get near the tumor cells.” As a result, we must create places for T cells to invade.”

Death receptors accomplish exactly what their name implies: when activated, they cause tumor cells to die by programmed cell death. They provide a potential workaround that might kill tumor cells while also paving the path for more effective immunotherapies and CAR T-cell treatment.

Creating medications that increase death receptor activity could be a powerful weapon against cancers. Despite medicinal firms’ success in targeting the Death Receptor-5, no Fas agonists have made it into clinical trials. These findings have the potential to change that.

“This is a definitive marker for bystander treatment efficacy of CAR T therapy. But most importantly, this sets the stage to develop antibodies that activate Fas, selectively kill tumor cells, and potentially support CAR T-cell therapy in solid tumors.”Jogender Tushir-Singh, associate professor, Department of Medical Microbiology and Immunology

The proper target
While Fas is important in immune cell regulation, Tushir-Singh and his colleagues suspected that if they located the proper epitope, they might be able to target cancer cells preferentially. After identifying this precise epitope, he and his colleagues may now create a new class of antibodies that can preferentially attach to and activate Fas, potentially destroying tumor cells.

Other research in animal models and human clinical trials has revealed that Fas signaling is critical to CAR T success, especially in genetically diverse malignancies. Tumors that are genetically diverse have a variety of cell types that respond differently to treatment.

A Fas agonist could cause a CAR-T bystander effect, in which the treatment eliminates cancer cells that lack the molecule targeted by the tumor-targeting antibody. In other words, activating Fas may damage cancer cells while improving CAR T effectiveness, giving tumors a one-two punch.

In fact, the study found that tumors with a mutant form of the Fas receptor epitope will not respond to CAR T at all. This discovery could pave the way for new diagnostics to determine which patients will benefit the most from CAR T-cell immunotherapy.

“We should know a patient’s Fas status — particularly the mutations around the discovered epitope — before even considering giving them CAR T,” she said. “This is a definitive marker for CAR T therapy bystander treatment efficacy.” Most importantly, this lays the groundwork for the development of antibodies that activate Fas, selectively target tumor cells, and may one day assist CAR T-cell treatment in solid tumors.”

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