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UMass researchers make strides in cancer and chronic infection research

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While many were away vacationing in the summer, a team of University of Massachusetts molecular biologists were busy making groundbreaking medical discoveries in the lab.

The team, led by Leonid Pobezinsky and research collaborator Elena Pobezinskaya, who is also his wife, published their research on July 24 in ELife. Their findings show a significant advance in understanding the body’s own immune defenses mediated by T-Cells, which play a major role in an organism’s defense and activate an immune response.

These discoveries can further be implemented to enhance current immunotherapy and the treatment of diseases with substances that stimulate the immune response. It may more effectively attack disease-causing agents such as invasive cancers and virally infected cells during chronic infections like HIV.

According to Pobezinsky, when people have cancer or chronic infection disorders like HIV, they need to enhance their immune systems. If someone has an immune disorder, where their immune system attacks their own body, they need to inhibit that faulty immune system.

Pobezinsky’s lab looks into ways to regulate the process by looking into immune system responses as well as the body’s use of T-cells.

When an organism is healthy, cytotoxic T lymphocytes (CD8 T-cells) are not active. But once they are activated—by an antigen, like a virus or another foreign substance—these CD8 T-cells can proliferate and evolve into cytotoxic cells. These cells have the effective function of killing target pathogenic cells, either infected or cancer cells.

The lab’s research shows how a small microRNA molecule, known as Lethal-7 (Let-7) serves as a molecular control hub, directing the cytotoxic function of CD8 T-cells. Let-7 does this by putting the brakes on the CD8 T-cells’ cell-killing activities.

Hence, the Let-7 microRNA—only 20 to 30 nucleotides long—acts as a switch that inhibits immune activity of CD8 T-cells and their tumor-killing ability. The levels of Let-7 molecules in CD8 T-Cells determine how effective T-cells can be in attacking a disease.

“If you think about it, it’s very simple,” said Pobezinsky. “T-cells, which are not active, they have a lot of this molecule [Let-7]. T-Cells, which become active and ready to kill target cells, don’t have much of this molecule.”

The team tested their hypothesis using genetically-modified mice. Some mice were manipulated to have a lot of the Let-7 molecule; some, very little. What they found was the CD8 T-cells in mice modified to have less Let-7 functioned better.

“We found our hypothesis was quite correct. Cells that lack Let-7 become very effective killers, and cells that maintain very high levels of Let-7 are unable to officiate into cytotoxic T lymphocytes and fail to kill target cells,” Pobezinsky said.

The team’s project started basically from scratch in 2014, according to Pobezinsky. It began after Pobezinsky did his post-doctoral research at the National Institutes of Health (NIH), researching CD8 T-cells. He was curious as to why these cells spread very high levels of the Let-7 microRNA molecule.

According to a University press release, “The research group led by the Pobezinskys includes his Ph.D. student and first author Alexandria Wells, UMass Amherst molecular biologist Michele Markstein, who provided the computational analysis to identify Let-7 targets and how Let-7 regulates the genome, and UMass Medical School immunologist Raymond Welsh, a specialist in cytotoxic CD8 T-cells who provided a viral model for testing differentiation in the presence of virus.”

Pobezinsky praised Wells for her effort, in particular, saying that without graduate student effort and interest, it would be very difficult to move the project forward.

“It’s very rewarding. There are definitely nights where you’ve been in lab for 12, 13 hours and you’re frustrated. You don’t know why this stuff isn’t working, but then you have that one experiment and you get results that makes it all worth it,” Wells said.

“Then taking what you’ve done in the lab and taking it to a mouse model, for instance, and get to see it actually cure cancer is pretty exciting. It reminds you why you do the work we do,” she said.

As for the future, Pobezinsky said the lab continues to look at how further differentiation of CD8 T-cells are led by the microRNA molecule Let-7.

One project the lab is taking on currently is how during an infection or tumor, pathogen specific CD8 T-cells generate memory T cells. After a pathogen, either a bacteria or virus, is cleared, a majority of killer T-cells die. Very few of these cells survive and form immunological memory, which would help conquer secondary reinfection of an organism.

He compared the process to vaccinations, in which vaccinations trigger an initial immune response, but memory cells that survived remember that antigen encounter. Pobezinsky’s team is looking to address if Let-7 molecules also play a role in this process by generating immunological memory, or the ability of the immune system to respond more rapidly and effectively to a pathogen that has been previously encountered.

Another team in his lab is focusing on how Let-7 can be modulated to develop new kinds of therapies.

Pobezinsky said genetic manipulations could completely remove Let-7 microRNA molecules from CD8 T-cells that become vicious killers called “super killers,” which kill 50 times more effectively than just regular T-killers.

“We’re thinking how we can actually lower the level of these molecules in order to make super killers in cancer patients and help them eliminate the cancer,” Pobezinsky said. “We think that it can really play nicely with existing therapies against cancer.”

Peter Chien, associate professor of biochemistry and molecular biology and the director of the Models to Medicine Center in the Institute for Applied Life Sciences, said that Pobezinsky’s work led to the award of  a $3.75 million grant from the Nonpareil miRNA Accelerator. The grant will allow Pobezinsky to translate his basic research toward enhancing efficacy of cancer immunotherapy.

“Dr. Pobezinsky’s work is a wonderful example of how basic curiosity driven research is critical for new insight into fundamental biology and human health,” Chien said.

The research was supported by a grant from the Multiple Sclerosis Society and UMass start-up funds. More on the published research can be found on the open access journal ELife, according to the UMass press release.

Caeli Chesin can be reached at [email protected] and followed on Twitter @caeli_chesin.

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