Targeting telomere damage offers new path to boost cancer immunotherapy

Tumors are stressful places for cancer-fighting immune cells. Low oxygen, high acid levels, and other stressors put strain on mitochondria, the cell's energy factories, leading to T cell exhaustion and poor cancer outcomes.

New research published in Immunity by researchers at the University of Pittsburgh found that, in mice, the toxic tumor environment causes mitochondria to generate reactive oxygen species (ROS) that travel to the nucleus and damage telomeres, driving T cells to a dysfunctional state.

The really exciting part about this research is that by preventing damage to telomeres via a targeted antioxidant, we can rescue T cell function. This opens the door to novel therapies to improve the effectiveness of cancer immunotherapies."

Dayana Rivadeneira, lead author, assistant professor in the Pitt Department of Immunology and UPMC Hillman Cancer Center

Rivadeneira and senior author Greg Delgoffe, professor in the Pitt Department of Immunology and UPMC Hillman, didn't set out to study telomeres. They had initially been looking at how damage to mitochondria can affect T cell function. But a collaboration with Patricia Opresko, professor in the Pitt Department of Pharmacology and Chemical Biology, and the late Marcel Bruchez, professor of biological sciences and chemistry at Carnegie Mellon University, led them to consider telomeric damage, too.

The researchers created mice endowed with a genetic system that, when exposed to far-red light, generates highly targeted oxidative damage either at telomeres or mitochondria.

"What we found was remarkable," said Delgoffe. "Whether we damaged the mitochondria or the telomeres, we got the same result: dysfunctional T cells. There is crosstalk between the engine of the cell and the brains of the cell, the mitochondria and the nucleus. This is something we didn't necessarily appreciate, at least in the immune system."

"When you damage the mitochondria, one of the first thing that gets damaged is the telomeres," Rivadeneira added. "And, likewise, when you damage the telomeres, they talk back to the mitochondria to initiate a program that tells the cell to shut down and become exhausted."

Because ROS - highly reactive oxygen molecules that cause cellular damage - were responsible for telomeric damage, Delgoffe and Rivadeneira hypothesized that ROS-neutralizing antioxidants could protect or restore T cell function. 

To neutralize ROS specifically at telomeres, they took mouse T cells and tethered an antioxidant protein to another protein that resides at telomeres. When they infused these T cells into mice with an aggressive form of melanoma, the animals had much better survival and smaller tumors than those given regular T cells.

According to the researchers, this antioxidant approach could be applied to CAR-T therapy, which involves taking a patient's T cells and genetically engineering them to better recognize cancer cells before reinfusing them.

"This research is highly translatable because this approach could easily be incorporated into standard CAR-T protocol," said Delgoffe. "While you're genetically engineering T cells to improve cancer-fighting capability, you could also make them bulletproof against oxidative damage."

Now, the researchers are working to develop a similar telomere-specific antioxidant approach for modifying human T cells, which they eventually hope to test in clinical trials.

In her newly launched lab, Rivadeneira also plans to investigate more broadly how telomere health influences the immune system and cancer outcomes. One area of interest is understanding how chemotherapy alters T cell function by damaging telomeres and whether this could influence whether patients respond to immunotherapy.