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TORONTO — Researchers have discovered a groundbreaking breakthrough in the fight against cancer: a specific protein segment capable of initiating cancer cell death.
The UC Davis Comprehensive Cancer Center team has identified an epitope on the CD95 cell receptor that triggers a cascade that prompts cells to undergo self-destruction. This discovery has significant implications for developing new therapeutic strategies to halt the proliferation of cancer cells.
The CD95 receptor, also known as Fas, has long been recognized as a “death receptor” responsible for inducing cell death. However, until now, this knowledge had limited practical application. The findings of this study were published in the esteemed peer-reviewed journal Cell Death & Differentiation.
“Our research has pinpointed the most critical epitope for cytotoxic Fas signaling and CAR T-cell bystander anti-tumor function,” stated Jogender Tushir-Singh, a senior author of the study and associate professor at UC Davis Health and School of Medicine. “Past attempts to target this receptor have been unsuccessful. However, with the identification of this epitope, there is now potential for targeted Fas therapy in tumors.”
An epitope refers to a group of amino acids or chemicals found on the surface of a molecule. These epitopes can be recognized by the body’s immune system and trigger a series of reactions, including protein activation and cell death. By selectively targeting this newly identified epitope on Fas, researchers can develop antibodies that bind to and activate Fas in cancer cells, thus inducing cell death.
Furthermore, this breakthrough may enhance the efficiency of existing cancer treatments by enabling cancer cell death as a side effect while targeting other areas of the tumor.
The Complexity of Cancer Treatment
Cancer treatment options include surgery, chemotherapy, and radiotherapy. However, when these approaches fail and cancer recurs, doctors often turn to immunotherapies, which aim to strengthen the immune system’s ability to fight cancer.
One example of immunotherapy is CAR T-cell-based therapy, where researchers modify a patient’s T-cells to target tumor cells. While effective for blood cancers like leukemia, this approach has had limited success against solid tumors such as ovarian, breast, and lung cancers due to the distinct microenvironments within these tumors.
“These ‘cold tumors’ present a challenge as immune cells struggle to reach the tumor microenvironment and provide therapeutic effects,” explained Tushir-Singh. “Regardless of the engineering efforts to activate immune receptors and T-cells, they cannot penetrate the tumor cells. Therefore, we need to create pathways for T-cell infiltration.”
The death receptor Fas may serve as the much-needed pathway into solid tumors. By enhancing the activity of death receptors, it could not only increase cancer cell death but also facilitate the delivery of therapeutics directly into the tumor.
‘Bystander Effect’
Researchers hope to develop antibodies targeting this epitope to induce cancer cell death. Additionally, identifying the presence of this epitope in a patient’s cells can offer insights into optimizing CAR T-cell therapy.
A drug targeting this specific epitope could generate a “bystander effect” when combined with CAR T-cell therapy. This means that even cancer cells lacking the CAR T-cell therapy’s primary target molecule can be eliminated by the drug targeting the newly identified epitope.
In previous studies, the bystander effect was hindered by receptors that inhibit cell death, resulting in reduced efficacy. Targeting antibodies to this epitope could overcome this limitation.
The study also revealed that patients with mutated versions of this epitope on their Fas receptors did not respond to CAR T-cell therapy, suggesting that it could serve as a biomarker for therapy effectiveness.
“Assessing a patient’s Fas status, particularly the mutations related to the identified epitope, should be a prerequisite for CAR T-cell therapy,” emphasized Tushir-Singh. “This epitope is a definitive marker for bystander treatment efficacy in CAR T therapy. More importantly, it paves the way for developing antibodies that selectively activate Fas, kill tumor cells, and potentially support CAR T-cell therapy for solid tumors.”
To date, no antibodies targeting Fas have progressed to clinical trials. However, this newfound understanding of effective death receptor activation holds promise for future advancements in cancer treatment.
