The human immune system is one of our least understood physiological systems, second only to the brain in its sheer complexity. From arthritis to Type I diabetes, developing a better understanding of our immune system is crucial to helping patients overcome severe diseases. Additionally, our immune systems play a fundamental role in the prevention of cancers. While individual cells frequently develop devastating genetic mutations, our immune system is astonishingly good at identifying these anomalous cells and destroying them.
However, when a cell develops mutations that promote uncontrolled growth and allow it to evade, or even co-opt, the immune system, cancer can develop. Because of this, many recent innovations in cancer treatment have focused on reprogramming or otherwise aiding the immune system in the battle against cancer. One such approach—adoptive cell transfer—focuses on the isolation, proliferation, and reintroduction of tumor-reactive killer (CD8+) T-cells. These cells have the capacity to recognize markers, also known as antigens, on the outside of tumor cells and destroy the cell. However, previous methods of isolating these cells have suffered from the inefficient methods to exclude so-called bystander T-cells, which are not reactive to tumor antigens.
A recent study from the Scripps Research Institute in San Diego outlines a new method for the precise identification of tumor-reactive killer T-cells (Liu et al.). Their method, FucoID, builds on previous research for cell labeling, where an enzyme facilitates the transfer of a fucose-biotin labeling molecule to cell surface sugars. The authors developed a system where one cell type, the bait cell, has this enzyme attached to its surface. When the bait cell interacts with a prey cell, its surface enzyme labels the prey cell by attaching the fucose-biotin conjugate. In practice, the bait cells are first incubated with the transfer enzyme, which adds itself to the surface of the bait cells. Then, the cells are incubated with the contents of tumor cells, allowing the bait cells to uptake tumor antigens and present them on their surface. Finally, a mixture of T-cells isolated from the tumor is added. If the T-cell is reactive to the tumor antigens, they will associate with the antigen-presenting prey cells and become labeled by the fucose-biotin molecule. Having been labeled, these tumor antigen-reactive T-cells are readily separated and proliferated for therapeutic treatment (Liu et al.).
Beyond pioneering this new technique for the study of immune cells, the authors also demonstrated the system’s ability to improve cancer outcomes in vivo (Liu et al.). The authors used a murine pulmonary tumor model with fluorescent labeling to visualize tumor size. The study compared the effectiveness of tumor isolated T-cells with the PD-1 protein, a previously identified marker correlated with tumor reactivity, to T-cells with PD-1 that were also fucose-biotin labeled through their new method. The mice were either treated with a saline control, PD-1+ cells, or PD-1+Biotin+ cells. The PD-1+ cells were only able to reduce tumor luminescence by 60%; the PD-1+Biotin+ reduced luminescence by 98%. Additionally, the control and PD-1+-treated mice all died by day 19 and 22 respectively, but the PD-1+Biotin+ all survived to day 23 with 20% surviving until the end of the experiment (Liu et al.).
Innovative systems like FucoID are crucial to furthering our understanding of the immune system and translating discoveries into meaningful therapies. Hopefully, FucoID will also be a success in the human clinical setting.
Liu, Zilei, et al. “Detecting Tumor Antigen-Specific t Cells via Interaction-Dependent Fucosyl-Biotinylation.” Cell, vol. 183, no. 4, 2020, doi:10.1016/j.cell.2020.09.048.
Last Fact Checked on November 29th, 2021.