Fatty "blast shield" masks a weakness in aggressive cancer cells
The body's immune cells do a tremendous job of pouncing on pathogens or dangerous cells that might do us harm, attacking them with proteins and enzymes that pick apart their protective membranes. One mystery surrounding these natural killer cells is why these attacks don't inflict damage on their own protective membrane at the same time. Scientists believe they have uncovered the answer in a "blast shield " made of fat, which was also found at play in some cancer cells and helped them evade the immune system's attacks.
The research was led by Columbia University scientists, who were investigating the ways immune cells work, hoping to uncover the biological mechanisms behind their self-preservation capabilities. How can they be so effective at taking out their adversaries with "toxic blasts," eliminating up to six infected or cancerous cells every day, while avoiding damage to themselves?
"I've been working on natural killer cells since the early 1990s, and every time I gave a talk about these cells, someone always asked that question," says study leader and immunology expert Jordan Orange.
Orange's colleague and graduate student Yu Li turned his attention to a double-layered membrane found on the outer of all cells, made of a type of fat called lipids. Studying these under the microscope, Li noticed that the membranes around immune cells were more orderly and densely packed with lipids than other cell types.
"There were a lot of hypotheses about why natural killer cells don't kill themselves during their attack on other cells, but they all proposed there might be a magic, unknown protein protecting these cells," Li says. "Based on biophysical considerations, I didn't think a protein would be strong enough to protect the cells. When I looked at the cells, I thought of lipids."
To test out his lipid theory, Li carried out experiments in which he subjected the membranes to a compound that weakens the lipid layers. This lower density and less orderly membrane left the immune cells largely unprotected from their own "toxic blasts," killing them off as well as the cells they were targeting.
Further investigations showed that when they are about to launch an attack, the immune cells make some preparations. This includes moving small granules packed with the deadly substances toward the outer edges of the membrane to release their payload. In doing so, their own dense lipid membrane breaks apart and merges with that of the immune cell, acting as a key structural reinforcement.
"In essence, Li found that the membrane turns into a blast shield," Orange says. "And the protection comes from the way the membrane's lipids are arranged. When the lipids are arranged in a more orderly fashion, more lipids can be packed into the membrane. The toxic substances simply can't find a way into the membrane."
Scientists know that some cancer cells are able to protect themselves from attacks from immune cells, and this blast shield may explain why. Li experimented with aggressive breast cancer cells known to exhibit this behavior and found that they also fortify their membranes in this way. When the compound was added to weaken the lipid layers, the cancer cells became vulnerable to attacks.
"We don't know yet if this is a general mechanism by which cancer cells resist natural killer cells," Li says. "If it is generalizable, we can start to think of therapies that disrupt the tumor cell membrane and make it more susceptible to attack by the immune system."
The research was published in the journal PLOS Biology.