Using the immune system to target, and combat, tumors is a promising cancer treatment. One unmet need in this field is the ability to identify useful tumor-infiltrating immune cells more quickly and precisely. Indeed, the re-activation and clonal expansion of tumor-specific antigen (TSA)-reactive T cells are critical to the success of these therapies. Now, a new technique developed at Scripps Research offers a platform that could propel personalized cancer treatments that have been hindered due to the challenges of isolating the most useful immune cells in patients.
The work is published in Cell in the article titled, “Detecting Tumor Antigen-Specific T Cells via Interaction-Dependent Fucosyl-Biotinylation.”
“In many new and emerging personalized cancer therapies, the key to success is finding the sometimes-elusive T cells that are directly targeting the tumor, then creating more of those cells outside of patients’ bodies and re-introducing them for tumor treatment,” said scientist Peng Wu, PhD, associate professor in the department of molecular medicine and senior author of the study. “With our simple method to detect and isolate tumor-reactive immune cells, my hope is that we can advance personalized immunotherapy treatments that are now either too costly or laborious to reach their potential.”
There are no reliable markers to specifically identify the repertoire of TSA-reactive T cells due to their heterogeneous composition. The researchers designed the method they call FucoID, named after the enzyme fucosyltransferase that plays a starring role in “tagging” the surface of sought-after immune cells so they can be seen and captured. The enzyme is loaded onto dendritic cells, a type of immune cell that presents tumor-specific material to the desired T cells. When the cells interact, the enzyme transfers a tag to the tumor-fighting cells so scientists can detect them with a fluorescent probe and extract them from the sample.
The authors write that, through this interaction-dependent labeling approach, “intratumoral TSA-reactive CD4 +, CD8 + T cells, and TSA-suppressive CD4 + T cells can be detected and separated from bystander T cells based on their cell-surface enzymatic fucosyl-biotinylation.” Compared to bystander tumor-infiltrating lymphocytes (TILs), “TSA-reactive TILs possess a distinct T-cell receptor (TCR) repertoire and unique gene features.”
In experiments involving mice, the approach successfully identified multiple types of so-called “tumor antigen-specific T cells,” including CD4+ and CD8+ T cells that infiltrate tumors and attack from within. These cells are central to certain cancer immunotherapies—including checkpoint inhibitors and treatments known as adoptive TIL transfer therapies.
“This approach removes a significant barrier to studying tumor-specific T cells and will be immensely useful for both basic scientists and clinicians,” said John Teijaro, PhD, associate professor in the department of immunology and microbiology and co-author of the study.
“This study also highlights how the highly collaborative environment at Scripps Research fosters innovative solutions to intractable problems.”
The FucoID process of isolating the appropriate cells takes only one day, compared with four or five weeks using current methods, according to Wu. “Once we isolate them, we can expand them into millions or billions of cells to construct a treatment or simply to study them,” he said.
Having the ability to quickly take stock of these cells in a patient can also help doctors predict therapeutic success or treatment progress, he added. And doing any of these things faster than today’s methods, which rely on bioinformatics or genetic manipulations, can make a big difference to patients.
Wu is now collaborating with clinicians at the University of California, San Diego, to use FucoID to isolate the desired T cells from human patient tumor samples, with the goal of eventually applying the platform to a clinical trial for a cancer treatment.
“We believe FucoID has the potential to be translated to a clinical setting for the detection and isolation of tumor-reactive immune cells, ultimately paving the way for lowering the cost and accessibility of personalized cancer treatment,” Wu said.
