Identifying cancer-recognizing immune cells on a large scale

T cells are a type of immune cell that can kill cancer cells. However, in many cancer patients, only a very small number of T cells are truly able to recognize cancer cells, and it can be difficult to identify the ones that can. Now, researchers from the Netherlands Cancer Institute have successfully developed a novel method that enables the identification of T cell receptors at an unprecedented scale.

T cell receptor (TCR) gene therapy offers a potent strategy to utilize the body's own immune cells in the fight against cancer. In this treatment, a patient's own T cells are modified in the laboratory to express TCRs that are tailored to recognize and attack cancer cells. Through their T cell receptors, these modified T cells can identify specific cancer antigens, enabling targeted therapy. However, harnessing T cells for cancer treatment has posed challenges, primarily stemming from the difficulty in identifying the precise T cell receptors that are capable of effectively targeting a patient's unique cancer cells.

Through extensive experimentation, the researchers devised a method that can functionally test thousands of TCRs in a single experiment. Their findings, recently published in Nature Biotechnology mark a significant advancement in the field. PhD student Ziva Moravec: "This previously wasn't possible due to both the high costs associated with synthesizing each TCR for experimental testing, and a general lack of techniques that allow testing of T cell receptors at large scale".

Collaborating with Rootpath, a company specializing in synthetic biology, the researchers from the group of John Haanen, in collaboration with Ton Schumacher, synthesized and tested thousands of TCRs found on T cells infiltrating patients' tumors. Moravec: "This is how we were able to find rare truly tumor-specific receptors - not only in melanoma samples, in which the number of tumor-recognizing T cells is relatively high, but also in samples of other cancers in which these cells are much scarcer".

This new method opens the door to personalized cancer treatment through the identification of tumor-specific TCRs, which in turn paves the way for advanced TCR gene therapy. Senior scientist Wouter Scheper: "Beyond its clinical applications, this research provides invaluable insights into the behavior of T cells within tumors. By distinguishing truly tumor-reactive cells from the ones we call bystander cells, we can deepen our understanding of T cell dynamics and responses to therapies, advancing knowledge on the role T cells in cancer".

Currently, the focus remains on the further exploration of the properties of T cells in different tumors. This will facilitate a better understanding of their behavior and responses to various therapies, including immune checkpoint blockade.

This research was financially supported by KWF Dutch Cancer Society, ZonMw, The Dutch Research Council (NWO) and the AVL Foundation.

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