Reinvigorating T Cells to Fight Disease

A research team is investigating ways to use microRNA to revive exhausted T cells.

T cells are essential immune system components, but sometimes, when faced with chronic infections or cancer, they get tired.

Erietta Stelekati, Ph.D., assistant professor at Sylvester Comprehensive Cancer Center and the Department of Microbiology and Immunology at the University of Miami Miller School of Medicine, is investigating ways to restore T-cell function, and she has a great lead – a microRNA molecule called miR-29a.

Helping T Cells Regain Function

Dr. Stelekati was first author on a PNAS-published paper that showed miR-29a could revive exhausted T cells and get them back on track, work she started as a postdoctoral researcher in the John Wherry Lab at the University of Pennsylvania. Dr. Wherry was senior author on the paper.

Now at the Miller School, Dr. Stelekati is leading efforts to better understand this microRNA and find better ways to treat chronic infections and cancer.

“We want to make these exhausted T cells regain their normal functions,” said Dr. Stelekati, “and we’re excited that miR-29a could be the way to make that happen.”

The T Cell’s Journey in Fighting Disease

The body has a reservoir of naïve T cells that are just waiting for a fight. When they encounter a pathogen or tumor cell, they transform into effector T cells, which quickly replicate to go on the offensive. Eventually, these effector T cells evolve into memory T cells, which stand ready to pounce on the same intruder if it ever comes back.

Unfortunately, when faced with chronic infections, cancer or other conditions, effector T cells can lose their most aggressive traits. While they don’t shut down entirely, they can enter a sleepy mode and don’t evolve into memory T cells, removing a significant immune weapon.

“For many decades, we have known that exhausted T cells express different molecules than effector and memory T cells,” said Dr. Stelekati. “We just did not know how to make them functional and long-term, persisting T cells again.”

MicroRNA to the Rescue

Messenger RNA carries coded information from DNA to ribosomes to make proteins, which do most of the work in and around cells. However, cells add an extra layer of gene regulation called microRNA. These molecules don’t code for proteins but rather target messenger RNA for removal. No messenger RNA means no protein, and whatever that protein was supposed to do will not get done.

“These microRNAs are incredibly busy,” said Dr. Stelekati. “One small microRNA can actually target hundreds or thousands of messenger RNAs, causing major changes in gene expression.”

Drs. Wherry, Stelekati and colleagues zeroed in on miR-29a and showed it is an excellent marker for memory T cells. Whether they were comparing memory T cells to naïve, effector, or exhausted T cells, miR-29a levels always distinguished the memory T cells. This molecule was obviously having a significant impact.

Further investigation produced two surprising findings. First, miR-29a works economically, affecting expression of a few, powerful T cell genes. And even though the microRNA was making T cells more active, it was turning off genes to add function.

“We were not really expecting that because, clearly, those cells have increased function,” said Dr. Stelekati. “Perhaps slowing these cells down protects them from overactivation and that generates a healthier immune response.”

Further Investigation of miR-29a

Dr. Stelekati has assembled a stellar team to dissect miR-29a function and potential applications. Xuebing Leng, a Ph.D. student who helped co-author the PNAS study, was attracted to the Stelekati lab to study immunology and perhaps identify more effective cancer therapies.

Leng is currently working to harness miR-29a to make immunotherapies called checkpoint inhibitors more effective. PD-1 protein protects T cells from overstimulation when a threat (cancer or chronic virus) is not eliminated. However, tumors co-opt these mechanisms to minimize the immune attack. Checkpoint inhibitors seek to restore T-cell efficacy but only work effectively in some cancer types. Leng hopes to expand that efficacy.

“We are combining miR-29a with anti-PD-1 therapy to see if we can get a synergistic effect against the cancer,” said Leng. “Also, we want to understand why some T cells respond to checkpoint blockade therapy but others do not. If we can determine that, we will be able to find ways to make these therapies more effective.”

Overall, Dr. Stelekati wants to understand the mechanisms that help miR-29a restore T-cell vitality. While the earlier research showed the microRNA makes T cells more active, the study was not designed to show what type of cells they actually become.

“The big question is whether we changed how these cells differentiate,” she said. “Are we now dealing with memory cells, exhausted cells that simply function better or are they something completely different? We need to figure that part out.”

Tags: Dr. Erietta Stelekati, microbiology and immunology, Sylvester Comprehensive Cancer Center