T Cell Rejuvenation for Disease Fighting

Erietta Stelekati, Ph.D., an assistant professor at the University of Miami Miller School of Medicine’s Sylvester Comprehensive Cancer Center and the Department of Microbiology and Immunology, is researching ways to restore T cell function and has a promising lead – a microRNA molecule called miR-29a.

Aiding T Cell Regeneration

Dr. Stelekati was the first author on a PNAS-published publication that demonstrated miR-29a could resuscitate fatigued T cells and bring them back on track, work she began as a postdoctoral researcher at the University of Pennsylvania’s John Wherry Lab. Dr. Wherry was the paper’s senior author.

Dr. Stelekati is now directing work at the Miller School to further understand this microRNA and identify new strategies to treat chronic infections and cancer.

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

The T Cell’s Journey Against Disease
The body possesses a stockpile of immature T cells poised for a fight. When they come into contact with a pathogen or tumor cell, they change into effector T cells, which rapidly proliferate in order to go on the offensive. These effector T cells eventually mature into memory T cells, ready to pounce on the same intruder if it returns.

When confronted with chronic infections, cancer, or other circumstances, effector T cells can lose their most aggressive characteristics. While they do not completely shut down, they can enter a dormant state and do not mature into memory T cells, losing a substantial immunological weapon.

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

MicroRNA Comes to the Rescue
Messenger RNA transports coded information from DNA to ribosomes, where it is translated into proteins, which do the majority of the work in and around cells. Cells, on the other hand, add an additional layer of gene control known as microRNA. These molecules do not code for proteins, but rather remove messenger RNA. Without messenger RNA, there will be no protein, and whatever that protein was supposed to do would not be completed.

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

Drs. Wherry, Stelekati, and colleagues isolated miR-29a and shown that it is a good marker for memory T cells. When memory T cells were compared to naive, effector, or fatigued T cells, miR-29a levels invariably distinguished the memory T cells. This chemical was certainly having an effect.

Two unexpected conclusions emerged upon further examination. First, miR-29a functions efficiently by influencing the expression of a few potent T cell genes. Even though the microRNA increased the activity of T cells, it also turned off genes to add function.

“We were not really expecting that because, clearly, those cells have increased function,” Dr. Stelekati said in a press release. “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 contributed to the PNAS study, was drawn to the Stelekati lab to investigate immunology and possibly find more effective cancer treatments.

Leng is now researching on using miR-29a to improve the efficacy of immunotherapies known as checkpoint inhibitors. When a threat (cancer or persistent infection) is not eradicated, the PD-1 protein protects T cells from overstimulation. Tumors, on the other hand, use these systems to counteract the immunological response. Checkpoint inhibitors aim to restore T-cell efficiency, however they are only successful in certain cancer types. Leng intends to broaden that effectiveness.

“We are combining miR-29a with anti-PD-1 therapy to see if we can get a synergistic effect against the cancer,” Leng went on to say. “Also, we want to understand why some T cells respond to checkpoint blockade therapy but others do not. If we can figure that out, we’ll be able to figure out how to make these medicines 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.”

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