Using live microscope imaging, researchers at the Peter MacCallum Cancer Centre in Melbourne have developed a world-first technique for visualising the precise moment a T cell delivers a killer blow to cancer cells, enabling them to define the stages of the kill at which things can go wrong.
The findings, published today in the Journal of Immunology, will allow the research team, led by Professor Joe Trapani and Dr Ilia Voskoboinik, to understand why the process — in which a killer T cell recognises a cancer cell, binds to it and delivers a deadly dose of hole-punching perforin proteins and deadly granzyme proteins — sometimes fails in people with depleted immune systems.
Dr Misty Jenkins, co-first author on the paper, says by using live-cell imaging in human tissue and mouse models, she and fellow co-author Dr Jamie Lopez are now able to identify the specific errors that explain why the immune system may not complete a kill.
‘Some killer T cells may fail to detect cancer cells, some T cells identify a cancer target but may fail to bind to it successfully, other T cells bind successfully but may not “punch” through the cancer cells’ membrane, while other T cells may deliver the hit of granzymes, but not enough to kill the cancer cell.
‘We knew killer T cells sometimes failed to take out their target, but now we can see the attack unfolding in front of our eyes, we can pinpoint when, and hopefully why, this failure occurs.’
The cutting-edge visualisation allowed the research team to articulate the fact it can take as little as 40 seconds for a T cell to complete a successful kill, much faster than previously thought, shedding new light on the power of the immune system to fight cancer.
Dr Jenkins says clearly visualising the killer interaction has also revealed that, while T cells are just as vulnerable to damage from attacks of T cells’, a T cell is unharmed when gathering toxic weaponry on its surface.
‘For the first time, we’ve been able to see that when a killer T cell is in “attack mode”, it’s outer membrane is not punctured by the perforin it has secreted, and it is not at risk of being killed by its own granzyme payload.
‘This research is an important milestone for better understanding how our immune system can protect us from cancer’.
View the research paper.