T cells are among our immune system’s most powerful weapons against cancer, yet many of their behaviors remain surprisingly underexplored. Now, Oncode Researchers have uncovered a population of T cells that literally cling to cancer cells - revealing a property that may significantly improve immunotherapy.
The study, led by Oncode Investigator Daniel Peeper (Netherlands Cancer Institute), shows that the highly active tumor-killing T cells are those that form tight clusters with cancer cells. These clusters, typically filtered out in standard laboratory analyses, turn out to be an overlooked yet highly active immune population. The findings have now been published in Nature.
Discovering the Sticking T Cells
The research team co-cultured melanoma cells with T cells to examine how they interact. What they observed was striking. “We found that T cells that specifically recognize tumor cells stick to them very tightly to form clusters,” says Oncode Researcher Sofía Ibáñez-Molero, co-first author of the study. “These T cells were much more effective at killing cancer cells than individual, unbound T cells.”
This observation triggered a pivotal question: if these clusters represent the highly active T cells, could they be isolated directly from a tumor? The breakthrough came when the team demonstrated exactly that. The interactions between active T cells and cancer cells are so strong that these clusters can be isolated straight from patient tumors, enabling researchers to identify active, tumor-recognizing T cells more quickly and accurately than current methods. In laboratory models and in mice carrying patient-derived tumors, these T cells from clusters proved up to nine times more effective at destroying cancer cells.
A Shift in Perspective
Until now, most cancer immunology research has focused on individual T cells. While this has yielded important insights, the new findings reveal that critical information was hiding in the cell pairs and clusters that standard workflows would typically discard. According to Oncode Researcher Johanna Veldman, senior postdoc and co-first author, these clusters also display unique characteristics that may help predict whether a patient will respond well to immunotherapy.
“One thing I like about this study is that the principle is so straightforward: it makes sense that active T cells need to firmly attach to cancer cells before they can kill them,” says Oncode Investigator Daniel Peeper. “And yet, we have long overlooked that this very property could help us identify and isolate the T cells that are highly effective against cancer cells. By purifying these active clusters from tumors, we may be able to significantly improve current TIL therapies and open the door to new immunotherapy strategies, making a real difference for patients in the clinic. This is exactly the kind of research Oncode supports, turning bold ideas into real opportunities for patients.”
Toward Improved TIL Therapy
The discovery has immediate implications for TIL therapy, in which T cells are harvested from a patient’s tumor, expanded in the lab, and then reinfused to attack cancer. Identifying the right T cells within the tumor is a major bottleneck in the process. The new approach - selecting T cells based on their physical attachment to cancer cells - offers a direct and intuitive way to isolate the most active tumor-killing cells. The researchers are now working to develop a protocol to isolate these clusters for use in clinical trials and to explore whether the distinctive features of these cells can guide new forms of immunotherapy.
Impact: A New Window Into Immune Activation
This discovery reframes how scientists think about immune–tumor interactions. By revealing that T cells often operate in tight contact with tumor cells - and that this adhesive behavior marks them as potent tumor killers - the study opens an unexplored avenue for improving cancer treatment. It creates a faster route to identifying highly potent T cells, may improve TIL therapy, and provides new opportunities for predicting patient responses to immunotherapy. The characteristic features of these clusters may also inform the design of new therapeutic strategies, where this physical behavior of T cells becomes a selectable trait.
Oncode Institute’s Role
This study and the development of the accompanying protocol were made possible through support from Oncode Institute, which financed the work through two TechDev funds. These resources enabled the team to fully characterize T-cell–tumor clusters, develop the method to isolate them, and then refine and optimize the procedure. Oncode Institute’s infrastructure and scientific support was pivotal for the project development and will continue to play a critical role in translating a biological insight into clinical application of this technology, with the aim of improving TIL therapy in patients. The institute also supported the protection of this innovation, resulting in two patent filings based on the newly developed method.
This research was funded by Oncode Institute, KWF Dutch Cancer Society, NWO, the European Research Council (ERC), and the AVL Foundation.