Scientists Use AI for Protein Design to Improve T-Cell Based Immunotherapies

A study published in Cell demonstrates how researchers have employed artificial intelligence-based protein design to create a novel synthetic ligand that activates the Notch signaling pathway, crucial for T-cell development and function.

These soluble Notch agonists can be broadly used to optimize clinical production of T-cells and advance immunotherapy treatments.

The Notch signaling pathway plays a key role in many cellular differentiation processes, including the transformation of human immune cells into T-cells that combat viruses and tumors. However, activating this pathway in a lab setting has been challenging.

To tackle this, researchers from the laboratory of George Daley, Dean of Harvard Medical School and Co-Founder of the Stem Cell and Regenerative Biology Program at Boston Children's Hospital, along with collaborators, engineered a soluble Notch agonist. This allows for T-cell production in a liquid suspension culture instead of on a flat "2D" surface.

The team utilized recent advancements in computational protein design using David Baker's Rosetta tool, which was partially recognized during his 2024 Nobel Prize win in Chemistry. This tool facilitates the design of proteins from scratch.

Research fellow Rubul Mout and colleagues in Daley's lab developed a panel of multivalent Notch ligands with varied geometries to test their ability for receptor activation.

The study found that trans-binding configurations were most effective in promoting Notch synapse formation, with receptor clustering at the cell-cell junction creating 'signaling hubs' for enhanced Notch activation.

"AI-powered protein design is a versatile platform we've used to develop synthetic molecules that aid in clinical T-cell production and enhance immune responses when administered in vivo," says Daley.

"We're enthusiastic about this approach as it targets T-cells towards tumors while stimulating their killing functions."

Mout, the lead author of the research, states: "Activating Notch signaling opens numerous possibilities in immunotherapy, vaccine development, and immune cell regeneration."

"However, what excites me most is engineering synthetic protein molecules using this technology to link T-cells with cancer cells while boosting their killing power and overcoming the immunosuppressive tumor environment. My goal is to develop more effective immunotherapies."