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Bringing tired lymphocytes back to life: A new hope for cancer immunotherapy?

Bringing tired lymphocytes back to life: A new hope for cancer immunotherapy?

New research is exploring ways to rejuvenate terminally exhausted T-cells
Representational Image | Shutterstock

The human body’s battle with cancer, like any battle, affects the soldiers that fight it. In the case of our bodies, these would be T-cells (lymphocytes), which are among the white blood cells that upkeep the body’s immunity.

During the course of a cancer’s development, T-cells reach a state of “exhaustion” over time, and end up with deteriorated function. The result, an irregular immune response, further compounds the problem.

Terminally exhausted T-cells have so far been written off as a lost cause, with no way of returning them to functioning capacity. However, a recent study done on lab mice by researchers from the University of Pittsburgh and UPMC has found a way to potentially reactive even the most terminally exhausted T-cells.

What are T-Cells

Born from stem cells in the bone marrow, T-Cells or T-Lymphocytes, [also known as thymocytes] are an important part of the immune system. They have been used to fight cancer in a therapeutic procedure known as T-Cell transfer therapy.

As of now, two immunotherapies exist that use T-Lymphocytes to combat cancer. One is Tumour Infiltrating Lymphocytes therapy, or TIL, where the Lymphocytes inside the tumour are extracted and tested to find which one detects cancer cells the best.

The second is CAR T-Cell Therapy, where the T-cells are changed in the lab to make proteins known as Chimeric Antigen Receptors. CAR proteins give T-Cells the ability to attach to certain proteins on the tumour, making it possible for a hostile immune response in the cancer cell.

T-Cell transfer therapy is mostly used in the treatment of melanomas. And it is in a study on lab mice having melanomas with T-cells ranging from early to terminal exhaustion, that researchers discovered that T-Cells with the most advanced levels of exhaustion still had the capacity to become functional again.

How does this work?

Immunosuppressants have been able to bring back T-Cells that were in the early stages of exhaustion. But once they reach a stage of extreme exhaustion, it was believed to be impossible to bring them back – until this study proved otherwise.

“People think about terminally exhausted T cells as a lost cause, that there’s no coming back from this state,” said the study’s co-senior author Amanda Poholek, Ph.D., assistant professor of pediatrics and immunology at Pitt’s School of Medicine and director of the Health Sciences Sequencing Core at UPMC Children’s Hospital of Pittsburgh. “But given the right circumstances — the T cell version of rest — we show that they can come back. This finding could have incredible potential for immunotherapy,” she said.

The study, published in Science Immunology, explains that a co-stimulatory signal and a T-Cell receptor are the two switches that activate a T-Cell. It was discovered that terminally exhausted T-cells suffered from insufficient co-stimulation. However, when the researchers used an antibody that binds to the 4-1BB co-stimulatory receptor, it increased gene expression, in turn enhancing activity of the T-cells.

The researchers also found that low oxygen (hypoxia) also contributed to impaired gene expression in terminally exhausted T-cells. A possible approach to reinvigorating these cells could include the use of drugs that target hypoxia, or co-stimulation pathways, or even engineering exhaustion-resistant CAR-T cells, the researchers say.

“Exhausted T cells have what it takes to be functional, but the tumour environment is set up for them to fail,” explained Delgoffe. “By restoring oxygen or improving co-stimulation, we can realize the full potential of these cells and potentially gain the benefits of a functioning, healthy immune system.”

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