Scientists have engineered new ‘supercharged’ immune cells that could attack prostate cancer more effectively. 

Researchers at UCLA and Stanford Medicine researchers, in collaboration with scientists from the University of Utah and Columbia University, have engineered a new class of ‘supercharged’ T cells that are stronger, longer lasting, and more precise at killing prostate cancer cells by fine-tuning how they physically interact with tumour cells. 

The team, collaborating within the network of the Parker Institute of Cancer Immunotherapy (PICI), introduced a natural ‘catch bond,’ a fishhook-like interaction that strengthens when cells pull against each other. This allows T cells to latch onto cancer cells more effectively when they attack, helping them recognise the tumour, stay engaged longer and deliver a more powerful and targeted immune response without damaging healthy tissue. 

The new approach represents an important step toward developing safer, more effective T cell therapies for prostate cancer and could potentially be adapted to treat a wide range of other tumours. 

“By engineering catch bonds, we aim to benefit more patients by overcoming immune tolerance,” said co-senior author Dr Owen Witte, Founding Director Emeritus of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and Co-Director of the PICI Center at UCLA. 

“By creating T cells that are stronger, longer lasting, and highly precise, the approach moves the field closer to safer and more effective adoptive cell therapies for patients.” 

How catch bond engineering ‘turbocharged’ T cells 

T cells are a powerful weapon in the fight against cancer, forming the basis of treatments such as CAR-T cell therapy and checkpoint inhibitors. This research centres on another type of immunotherapy approach called T cell receptor (TCR) therapy, which engineers T cells to recognise specific proteins on cancer cells, allowing for highly targeted attacks. 

Many of these proteins, however, are ‘self-antigens,’ or molecules normally found in the body. To prevent these T cells from attacking healthy tissue, the immune system naturally eliminates the strongest cancer-fighting T cells during development. This leaves behind weaker T cell receptors that may struggle to recognise and destroy tumours, particularly those that have learned to evade immune defences. 

To overcome this challenge, researchers focused on fine-tuning naturally occurring T cell receptors to strengthen their ability to recognise a common prostate cancer protein called prostatic acid phosphatase (PAP), which is commonly expressed on prostate tissue and prostate tumours.  

The team also identified a naturally weak TCR, known as TCR156, that could detect PAP but was not strong enough to effectively kill cancer cells. 

Using a novel technique called catch bond engineering, a concept developed by the Garcia Lab at Stanford Medicine, the researchers ‘turbocharged’ the T cells, allowing them to attack prostate cancer cells more effectively. 

Tumour control ‘can be linked to a single molecular bond’

In the body, T cells form brief, mechanical bonds with their targets, known as catch bonds, which help them sense and respond to threats. By altering just one or two amino acids in the T cell receptor, the scientists were able to strengthen these bonds while preserving the T cells’ natural ability to recognise their specific target. 

“Using advanced structural studies at atomic resolution, we were able to demonstrate how a tiny change, just one amino acid in the interface between a T cell receptor and a prostate cancer protein called PAP, can extend the bond lifetime, dramatically boosting the T cell’s ability to kill tumours in living models,” said Dr Xiaojing Tina Chen, co-first author of the study and a Postdoctoral Scholar in the Department of Molecular and Cellular Physiology at the Stanford School of Medicine. 

“This work shows that tumour control can be linked to a single molecular bond,” added co–first author Dr Zhiyuan Mao, a Postdoctoral Scholar in the Department of Microbiology, Immunology & Molecular Genetics and the Department of Molecular and Medical Pharmacology at the David Geffen School of Medicine at UCLA.  

The study demonstrates that catch bond engineering can make T cells much stronger against prostate cancer while avoiding the risks of traditional T cell receptor engineering, including attacks on healthy tissue. 

The findings also suggest a new way to predict which T cell therapies will succeed. By measuring how long T cells form bonds with tumour targets under mechanical force, a method called the biomembrane force probe, researchers can more accurately predict which engineered cells will be most effective in eliminating tumours. 

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