We have a lot to thank our immune systems for, as they remain ever-vigilant to protect us from cancer and infections. But exactly how do immune cells avoid wiping themselves out while attacking invaders? Researchers at Australia’s Peter MacCallum Cancer Centre and the University College London (UCL) have now found that they create a tough shield around themselves, and this discovery could lead to new cancer therapies.
Cytotoxic T lymphocytes (CTLs) are a type of immune cell that hunts down cells that are cancerous, infected or otherwise damaged. Once they latch onto the target, they use a protein called perforin that punches holes into the outer membrane of the cell. With that protective layer compromised, toxic molecules can enter and kill the troublesome cell.
But there’s a long-standing mystery in just how that works. By all accounts, CTLs should fall victim to their own attacks, but they always win the battle, and scientists haven’t been sure why that is.
For the new study, the researchers at Peter Mac and UCL set out to investigate. The answer, it seems, lies in the outer membrane itself. Not only is the membrane of CTLs more dense than in the target cells, but some of the lipid molecules that make them up are negatively charged. That allows them to capture the perforin proteins, preventing them from doing any damage.
“All cells in our body are surrounded by a membrane made up of millions of tiny lipid molecules,” says Ilia Voskoboinik, senior author of the study. “We found that the lipids in the membranes of CTLs are more tightly packed together compared to the cells that they are trying to kill. The more densely packed the lipids, the more impenetrable the membrane is to the action of perforin.”
To check this mechanism, the researchers artificially disrupted the lipids in the membranes of CTLs. Sure enough, these immune cells lost some of their resistance to perforin. The team says that some cancer cells may harden their own membranes as a defense mechanism – and undoing this could potentially lead to new anti-cancer therapies.
“The efficacy of current immunotherapy approaches relies on the ability of CTLs to kill tumor cells through the activity of perforin,” says Jesse Rudd-Schmidt, joint-lead author on the study. “If some cancer cells can reorganize their outer membranes to resemble the tightly packed and negatively-charged membranes of CTLs, this could protect them from being killed by the immune system. This could in part explain some of the large variability in patient response to cancer immunotherapies.”