At the center of the immune system are T cells, which act like a security team trained to recognize and eliminate anything harmful such as viruses, bacteria, and even cancer cells. But how do these guards know who the bad guys are?
That鈥檚 the question Prof. Raquel Cuella Martin and Prof. Heather Melichar at 黑料不打烊 University are trying to answer through their D2R-funded research. Their project, Deep mutagenesis approaches to decode T cell receptor-antigen recognition, aims to better understand how T cells detect threats鈥攖hey will use this knowledge as well as the combination of genetics, artificial intelligence (AI) and immunology to develop a new approach to improve cancer treatments.
How do T cells work?
T cells have special receptors that act like keys. These keys are designed to fit into specific 鈥渓ocks鈥� (called antigens) on other cells. When a match is found, the T cell knows it鈥檚 found a target and launches an immune response.
The challenge? There are millions of combinations of keys and locks. Predicting which T cell receptor will bind to which antigen is complex鈥攁nd critical for designing treatments that hit the right targets without damaging healthy cells.
鈥淚t鈥檚 not just about giving T cells more targets,鈥� says Prof. Melichar, an immunologist. "The quality of the target matters more than the quantity. It's not the number of targets you can tell the T cells to go after, but the quality of those targets."
Choosing the right targets
Prof. Cuella Martin, an expert in genome engineering, explains, 鈥淐reating effective vaccines really depends on how well we harness the power of T cells. To do that, we need to understand how the small piece of protein included in a vaccine鈥攖he antigen鈥攖riggers an immune response. That鈥檚 a key piece of the puzzle.鈥�
To address this, they are creating a platform that tests how different T cell receptors interact with various antigens. This testing method, called "deep mutagenesis," allows researchers to test millions of combinations and observe how well they work. This generates a large amount of data, which is analyzed using artificial intelligence. The AI helps identify patterns and predict which receptor-antigen matches are most likely to lead to effective, safe immune responses.
"We need platforms and prediction algorithms that enable us to choose the right targets for T cells," says Prof. Melichar.
Prof. Cuella Martin adds, 鈥淲e鈥檙e still in the early stages, it鈥檚 a proof-of-concept study for now鈥攂ut the goal is to eventually produce enough data to say: 'This antigen is likely to generate the strongest T cell response,' or 'This T cell receptor is most likely to recognize and kill tumor cells.' That knowledge is crucial for both infectious disease vaccines and cancer immunotherapies.鈥�
Inclusivity in research
Many cancer treatments do not work the same for everyone. One reason is that people have different genetic makeups, especially when it comes to the immune system. The proteins that help T cells recognize antigens, called HLA molecules, vary from person to person.
Historically, most research focused on HLA types found in people of European descent. That means people from other backgrounds may not have benefited from treatments based on that data.
To help change that, Profs. Cuella Martin and Melichar are making sure their research includes T cell-HLA pairs found in all individuals regardless of race or ethnicity.
鈥淚nclusivity in research design is crucial,鈥� says Prof. Cuella Martin. 鈥淲e need to think about all populations and ensure our treatments are effective across diverse genetic backgrounds."
What鈥檚 next?
In the short term, the team hopes to identify the "just right" T cell receptors鈥攐nes that are strong enough to fight cancer cells but do not harm healthy cells. This balance, often called the "Goldilocks zone," is key to creating safe and effective therapies.
In the long-term, the research could redefine how cancer vaccines are designed. Prof. Cuella Martin explains "I do think our project has broad implications鈥攏ot just for RNA vaccines, but for many kinds of RNA and non-RNA therapies. At the heart of it, our project is about understanding which antigens best trigger a T cell response, and which T cells are best suited to respond. That鈥檚 essential for improving therapies across the board鈥攆rom infectious disease to cancer."
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Learn more about Prof. Cuella Martin's D2R-funded project by watching the video below:听
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