Cells get stressed too and when they do, cancer therapies fail. A UNC researcher may be on the cusp of finding a solution to T cell exhaustion.
When the immune system experiences prolonged cell stress, immunotherapy fails. Immunotherapy uses the body’s own immune cells, such as T cells or B cells, to attack and destroy cancer cells. The only problem is that immune cells can become exhausted from the fight.
“My lab focuses on the concept that immune cells in solid tumors experience profound metabolic stress, and we can help cells overcome cell stress to enhance immunotherapy,” said Jessica Thaxton, an associate professor in the Cell Biology and Physiology Department and the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill.
Thaxton and her team discovered a conserved stress sensing pathway in immune cells that, if inhibited, halts immune cell stress and even helps immune cells form a molecular memory of cancer. Her team recently received an 800,000-dollar Translational Award from the V Foundation to expand their research discoveries at the bench into patient samples in hopes of generating a new immunotherapy to reverse T cell exhaustion.
Cancer causes a different kind of stress
Scientists know the hallmarks of an exhausted T cell largely by studying models where T cells fight viral infections. “T cells in a tumor microenvironment, though, create a unique slew of intracellular metabolic dysregulation,” said Thaxton. Solid tumors are hypoxic, meaning they have poor oxygen supply, which adds an immense amount of stress to healthy cells. Markers of T cell exhaustion identified in a viral setting have generally not worked effectively to treat cancer because the molecular stress in cancer is more severe.
Thaxton and her team found a key protein in evolutionarily conserved cell stress pathways called activating transcription factor 4 (ATF4) that they believe could be the lynchpin in controlling immune cell stress in a tumor microenvironment. To test their hypothesis, Thaxton’s team labeled mouse tumors with a hypoxia stress marker and a marker for ATF4.
“Our most unexpected finding was that the cell stress response, measured by ATF4 expression in tumors, directly overlapped with areas of hypoxic stress. Where hypoxia was high in tumors, ATF4 was similarly high. We were able to observe cell stress in the spatial context of the tumor, and it was beautiful,” said Thaxton. “Immediately, we knew, any immune cell that got close to that region would be high in ATF4 and become defective.”
She shared her results with Robert Ferris, the director of the UNC Lineberger Comprehensive Cancer Center, who had just completed a next generation clinical trial of doublet immune checkpoint inhibitor therapies for patients with head and neck cancer. Remarkably, Thaxton and Ferris found that T cells in tumors from patients that were non-responsive to treatment in Ferris’ trial also had an ATF4-directed molecular stress signature.
Potential for a new global cancer drug
The V Foundation Award will empower Thaxton to translate her research on ATF4 expression and inhibition in mice to patients with head and neck cancer, ultimately laying the foundation for the development of a first-in-class ATF4 inhibitor drug. Thaxton’s team is looking into ISRIB, a relatively new compound originally described in 2017, with the potential to act as a non-toxic inhibitor of cell stress.
Several biopharmaceutical companies are already manufacturing the drug for clinical trials related to neurodegenerative diseases, where cell stress can lead to protein misfolding and become particularly problematic. “Our goal is to partner with one of these companies and move into a clinical trial,” said Thaxton.
When her team administered ISRIB in mice, it significantly reduced ATF4 expression in immune cells and reshaped the mice’s adaptive immune response to cancer. “We paired the drug with immune checkpoint inhibitors, and the tumors went away. The mice gained what is called immunological memory, which means they were protected from re-emergent cancer,” said Thaxton. This indicates, the drug may be useful in helping to train patients’ immune cells to guard against metastatic disease.
“One reason I love being an immunologist and why I love studying the cell stress response is because, in targeting a stressful metabolic microenvironment in tumors, there is an immense opportunity to translate new therapies to multiple solid tumor types with similar metabolic stress,” said Thaxton. According to her team’s preliminary data, there is a shared stress signature in immune cells across human lung, melanoma, and head and neck cancers.
If this signature could be safely inhibited, then it could expand immunotherapy possibilities across multiple cancer types. The V Foundation award is the first step to exploring this possibility. “As a translational researcher who is very clinically minded, I am excited to see if we can get a drug to patients,” said Thaxton.
References
- del Mar Alicea Pauneto, C., Riessenberg, B.P., Gandy, E.J., et al. Intra-tumoral hypoxia promotes CD8+ T cell dysfunction via chronic activation of integrated stress response transcription factor ATF4. Immunity 58, 1-16 (2025)
- Chou, A., Krukowski, K., Jopson, T., et al. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. PNAS 114(31), E6420-E6426 (2017).
Written by Tiffany Garbutt, PhD