A research team has identified a way to trigger programmed cell death which could open the door for improved cancer treatments.
CD95 receptors, also known as Fas, are called death receptors. These protein receptors reside on cell membranes. When activated, they release a signal that causes the cells to self-destruct.
Modulating Fas may allow chimeric antigen receptor (CAR) T-cell therapy to target solid tumours like ovarian cancer.
The team have taken a step towards that in the discovery of a crucial epitope – a protein section that can activate the larger protein – which may activate the CD95 receptor that can cause cells to die.
The findings from the UC Davis Comprehensive Cancer Center were published on October 14 in the Nature journal Cell Death and Differentiation.
“Previous efforts to target this receptor have been unsuccessful,” said senior author of the study Jogender Tushir-Singh, an associate professor in the Department of Medical Microbiology and Immunology .
“But now that we’ve identified this epitope, there could be a therapeutic path forward to target Fas in tumours.”
Finding better cancer therapies
Cancer is generally managed with surgery, chemotherapy and radiotherapy. These treatments may work initially, but in some cases, therapy-resistant cancers often return.
Immunotherapies, such as CAR T-cell-based immune therapies and immune checkpoint receptor molecule activating antibodies, have shown promise to break this cycle.
But they only help an extremely small number of patients, especially in solid tumours such as ovarian, triple-negative breast cancer, lung and pancreas.
T cells are a type of immune cells. CAR T-cell therapies involve engineering patient T cells by grafting them with a specific tumour-targeting antibody to attack tumours.
These engineered T cells have shown efficacy in leukaemia and other blood cancers but have failed repeatedly to provide success against solid tumours.
“These are often called cold tumours because immune cells simply cannot penetrate the micro-environments to provide a therapeutic effect,” said Tushir-Singh.
“It doesn’t matter how well we engineer the immune receptor activating antibodies and T cells if they cannot get close to the tumour cells. Hence, we need to create spaces so T cells can infiltrate.”
Death receptors do precisely what their name implies — when targeted, they trigger programmed cell death of tumour cells.
They offer a potential workaround that could simultaneously kill tumour cells and pave the way for more effective immunotherapies and CAR T-cell therapy.
Developing drugs that boost death receptor activity could provide an important weapon against tumours.
However, though drug companies have had some success targeting the Death Receptor-5, no Fas agonists have made it into clinical trials. These findings could potentially change that.
The right target
While Fas plays an essential role in regulating immune cells, Tushir-Singh and his colleagues knew they might be able to target cancer cells selectively if they found the right epitope.
Having identified this specific epitope, he and other researchers can now design a new class of antibodies to selectively bind to and activate Fas to potentially destroy tumour cells specifically.
Other research in animal models and human clinical trials has shown that Fas signalling is fundamental to CAR T success, particularly in tumours that are genetically heterogeneous.
Genetically heterogeneous tumours have a mix of different cell types, which can respond differently to treatment.
A Fas agonist could generate a CAR-T bystander effect, in which the treatment destroys cancer cells that lack the molecule the tumour-targeting antibody is designed to hit.
In other words, activating Fas may destroy cancer cells and improve CAR T efficacy, a potential one-two punch against tumours.
In fact, the study showed tumours with a mutated version of the epitope of Fas receptors will not respond to CAR T at all.
This finding could lead to new tests to identify which patients will benefit 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,” Tushir-Singh said.
“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 tumour cells, and potentially support CAR T-cell therapy in solid tumours.”
