Prostate cancer: scientists engineer T cells with stronger tumor bonds

Researchers at UCLA and Stanford used catch bond engineering to change one or two amino acids in a T cell receptor that recognizes prostatic acid phosphatase (PAP), producing engineered T cells that showed improved tumor killing and persistence in laboratory and mouse models while avoiding detectable attacks on healthy tissue.

Researchers at UCLA and Stanford Medicine, working with teams at the University of Utah and Columbia, report engineered T cells that more effectively target prostate cancer. The study, published in Science, focuses on strengthening brief, mechanical interactions called catch bonds between T cell receptors and a prostate protein called prostatic acid phosphatase (PAP). Rather than simply increasing static binding strength, the team altered one or two amino acids in a naturally weak receptor (TCR156) to lengthen bond lifetime under force while preserving specificity. In laboratory and mouse models, these modified T cells showed improved tumor killing, greater persistence, and resistance to exhaustion without apparent off-target attacks on healthy tissue. Key findings: - Catch bond engineering altered one or two amino acids in TCR156 to create stronger, longer-lived mechanical bonds with PAP. - Structural and computational studies indicated the mutations did not change overall TCR shape but primed a new interaction during dynamic engagement with the tumor protein. - Engineered T cells showed longer contact with cancer cells, greater secretion of Granzyme B, IFNγ and TNFα, increased proliferation, and resistance to exhaustion in laboratory tests. - In mouse models, modified T cells delayed or halted tumor growth while unmodified T cells showed little effect. - Measurements of bond lifetime under force using a biomembrane force probe were better predictors of tumor-killing ability than conventional binding strength measures. Summary: The authors present catch bond engineering as a way to make T cell receptors stronger, longer-lasting, and highly specific against a prostate cancer antigen, and they report laboratory and animal evidence of enhanced tumor control without detectable healthy-tissue targeting. Undetermined at this time.