Scientists Claim to Identify ‘Switch’ to Kill Cancer, Possibly Revolutionizing Treatment

A research team has identified a key protein fragment that, in a dual action, selectively triggers the self-destruction of cancer cells and enhances the efficacy of CAR-T immunotherapy for solid tumors. The microenvironment and heterogeneity of solid tumors often hinder the infiltration of CAR-T cells enough to cause destruction. The identification of this new therapeutic target provides a promising avenue to overcome this obstacle.

Surgery is typically the first step in treating solid tumors, then chemotherapy or radiotherapy. However, these treatments often result in only temporary remissions, and tumors may regrow later. Immunotherapies such as CAR-T have shown promise for prolonged remission but unfortunately can only help a very limited number of patients.

CAR-T therapy involves genetically modifying the patient’s T cells to recognize and eliminate tumors. While the therapy has shown some effectiveness in treating leukemia and other blood cancers, it struggles significantly to impede the progression of solid tumors. The challenge lies in the highly immunosuppressive microenvironment of these tumors, hindering T-Cell infiltration. “These are often called cold tumors because immune cells simply cannot penetrate the microenvironments to provide a therapeutic effect,” explains the co-author of the new study, Jogender Tushir-Singh, from the University of California, Davis. Additionally, some tumors are genetically heterogeneous, containing multiple cell types, each reacting differently to treatment.

To address these challenges, Tushir-Singh and his colleagues turned to proapoptotic receptors, notably CD95, which activates programmed cell death, or FAS (Fibroblast Activated Sequence). Targeting these receptors has the potential to activate the self-destruction of tumor cells and clear the path to facilitate CAR-T cell infiltration. “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,” explains the expert.

Illustration showing CAR-T immunotherapy.
Illustration showing CAR-T immunotherapy. Image: Gustave Roussy Institute.

A Dual Therapeutic Target

The Fas receptor belongs, along with Death Receptor-5 (DR5), to a superfamily of alpha receptors for tumor necrosis. Binding with their activation antibodies (agonists), they initiate apoptotic signaling by assembling transmembrane protein complexes. While many clinical trials have targeted DR5, the targeting of FAS is much less explored.

FAS levels are particularly high in solid tumors, including those affecting the ovaries. Furthermore, FAS signaling is essential for maintaining the elimination of tumor cells by T lymphocytes and a healthy immune homeostasis.

Previous research has demonstrated that FAS signaling is crucial for the success of CAR-T therapy, especially for genetically heterogeneous tumors. This implies that a Fas agonist could enhance CAR-T therapy, allowing it to eliminate tumor cells lacking the antigens it is supposed to target. However, “Previous efforts to target this receptor have been unsuccessful. But now that we’ve identified this epitope, there could be a therapeutic path forward to target Fas in tumors,” suggests Tushir-Singh.

he Fas-specific epitope enhances CAR-T therapy by eliminating
The Fas-specific epitope enhances CAR-T therapy by eliminating a negative and positive antigen tumor cell, shown in gold color on the right and left, respectively. Image: University of California-Davis.

In the new study, Tushir-Singh and his colleagues tested the idea that cancer cells could be targeted much more precisely if the important FAS targeting epitope (a protein fragment of the receptor) was found. “It is imperative to discover the most critical and regulatory targeting epitope of the FAS receptor for the next generation of immunotherapeutic products capable of selectively targeting tumors,” they state in their study published in the journal Cell Death & Differentiation. In other words, an antibody that binds to this epitope specifically would act as a switch, activating it.

In this vision, the researchers analyzed models of human and animal ovarian tumor cell lines. They sought to determine if, like that of the DR5 receptor, the FAS pathway utilizes a regulatory motif of a “positively charged residue” epitope (PPCR) to cluster transmembrane receptors and activate them optimally. That is, engagement of the PPCR epitope is crucial to maximize the signaling of the FAS agonist.

After analysis, the team identified a critical PPCR fragment of FAS in a cysteine-rich region. Two new antibodies binding to the fragment were particularly effective in efficiently triggering apoptosis of tumor cells while paving the way for CAR-T cells. It was also observed that cells with a mutated version of the epitope did not respond at all to CAR-T therapy. This implies that the FAS status of patients should be determined before the administration of this therapy.