A research team from the UC Davis Comprehensive Cancer Center has identified a crucial epitope (a protein section that can activate the larger protein) on the CD95 receptor that can cause cells to die. This new ability to trigger programmed cell death could open the door for improved cancer treatments. CD95 receptors, also known as Fas, are called death receptors. These proteins reside on cell membranes and when activated, they release a inner signal (enzymes and second messengers) that causes the cells to self-destruct. Modulating Fas may also extend the benefits of chimeric antigen receptor (CAR) T-cell therapy to solid tumors like ovarian cancer. Previous efforts to target this receptor have been unsuccessful. But now that scientists identified this epitope, there could be a therapeutic path forward to target Fas in tumors
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 tremendous promise to break this cycle. But they only help an extremely small number of patients, especially in solid tumors such as ovarian, triple-negative breast cancer, lung and pancreas. T-cell therapies involve engineering patient T cells by grafting them with a specific tumor-targeting antibody to attack tumors. These engineered T lymphocytes have shown efficacy in leukemia and other blood cancers but have failed repeatedly against solid tumors. The reason is that tumor microenvironments are good at keeping T cells and other immune cells at bay.
These are often called “cold tumors” because immune cells simply cannot penetrate the microenvironments to provide a therapeutic effect. It doesn’t matter how well we engineer the immune receptor activating antibodies and T cells if they cannot get close to the tumor 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 tumor cells. They offer a potential workaround that could simultaneously kill tumor 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 tumors. However, though drug companies have had some success targeting the Death Receptor-5 (DR5), no Fas agonists have made it into clinical trials.
These findings could potentially change that. 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 tumor cells specifically. Other research in animal models and human clinical trials has shown that Fas signaling is fundamental to CAR T success, particularly in tumors that are genetically heterogeneous. Heterogeneous tumors 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 tumor-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 tumors. In fact, the study showed tumors with a mutated version of the epitope of Fas receptors will not respond to CAR T at all. This finding could sets the stage to develop antibodies that activate Fas, selectively kill tumor cells, and potentially support CAR T-cell therapy in solid tumors. But most importantly, this lead to new tests to identify which patients will benefit most from CAR T-cell immunotherapy.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Mondal T, Gaur H et al. Cell Death Differ. 2023 Oct 14; in press.
McKenzie C et al. Mol Ther Nucleic Acids. 2023 Apr; 32:603-621.
Bajgain P et al. Cancer Immunol Res. 2022;10(11):1370-1385.