In first-of-its-kind groundbreaking research, a team of scientists from the University of Massachusetts Amherst have analyzed and described what they call the “mosquito effect,” which sheds light on how specific pathogens, such as cancerous tumor cellsthey can outsmart the body's immune system.
The results of the study were published in Frontiers in Immunology.
Mosquito effect: what is it?
Just as mosquitoes ingest the blood of their host, the T cells of the immune system incorporate cytoplasmic material from tumors into their own cytoplasm. While it has long been known that many cell types can transfer cellular material from one to another, cytoplasmic transfer has never been observed in T cells, which is why it is called the mosquito effect.
Subsequent single-cell RNA (scRNA) sequencing shows that the cytoplasm of tumor cells alters the machinery responsible for protein coding in the host T cell. Research into the mosquito effect represents an important step forward in understanding how tumors can successfully evade the immune system, and therefore a step towards more effective treatments.
One of the great mysteries of medicine is how some pathogens manage to suppress the immune system to spread wildly. The immune system is made up of many different parts, but among the most important are T cells, which identify and attack pathogens, and regulatory T cells, which tell the T cells when it is safe to stop attacking, limiting the collateral damage to the immune system.
Yet, cancerous tumor cells have figured out how to short-circuit the immune system, with often catastrophic results for healthy tissue. How exactly tumor cells do this is not known, but, says Leonid Pobezinsky, associate professor of veterinary and animal sciences at UMass Amherst and senior author of the paper, said of the mosquito effect: “we have observed for the first time that T cells and regulatory T cells suck up some of the tumor cytoplasm and integrate it into their own.”
To make the discovery of the mosquito effect, Pobezinsky and his team, including first author Kaito Hioki, a graduate student in veterinary and animal sciences at UMass Amherst, and Elena Pobezinskaya, a research assistant professor also in veterinary and animal sciences animals at UMass and co-senior author of the study. Cancer cells engineered to produce an ultra-bright fluorescent protein called ZsGreen.
They then introduced the bright green tumor cells into a mouse model. After eight days, the model's tumor-infiltrating immune cells were collected and analyzed using state-of-the-art equipment in the flow cytometry laboratory at UMass Amherst's Institute for Applied Life Sciences.
“What we saw was surprising,” says Pobezinskaya. “The T cells were bright and uniformly green in color, which tells us that the tumor cytoplasm had been widely distributed throughout the T cell.”
Even more surprising was seeing the regulatory T cells light up too. The team found that the cells that shone the brightest were the ones most exhausted from fighting the tumor. Finally, the team determined that the transfer of cellular material requires tumor cells and the immune system to come into physical contact with each other.
“We know that cancer cells use different ways to suppress the immune system,” says Hioki. “We now also know that T cells incorporate part of the tumor into their cytoplasm, and that less aggressive immune cells have most of the tumor cytoplasm inside them. What we don't know is why. Do T cells look for food? Are they trying to observe and adapt to their new environment by absorbing parts of other cells? And finally, is the tumor hijacking this mechanism to turn off T cells?” These questions are all next steps for the authors to better understand the mosquito effect.
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