Co-first authors Hao Shi, PhD, and Yan Wang, PhD, both of the St. Jude Department of Immunology, with corresponding author Hongbo Chi, PhD, St. Jude Department of Immunology chair.
Immunotherapy, which uses a patient’s immune system to treat disease, has increased survival for some adults and children with cancer. However, it has had limited success against many pediatric solid tumors, in part because T cells can become functionally impaired or “exhausted.” St. Jude Children’s Research Hospital scientists today published results in Nature showing that the gene ZMYND8 is a major regulator of CD8+ T-cell exhaustion. Results further showed that removing the gene improves anti-tumor and anti-viral responses on its own, but also shows potential synergy in combination with immunotherapy.
The immune system uses CD8+ T cells to attack virally infected or cancerous cells. However, when CD8+ T cells are exposed to diseased signals for too long, such as from solid tumors or chronic viral infections, they can become overstimulated. That overstimulation causes CD8+ T cells to receive suboptimal activation by a T-cell stimulating signal called interleukin-2 (IL-2), and T-cells enter an exhausted state with limited function, unable to stop the tumor or infection from progressing. St. Jude investigators searched for the molecular link between overstimulation and exhaustion to see if they could prevent exhaustion and increase immune control of these diseases. They found their answer in ZMYND8.
“Now we may have a way to overcome CD8+ T-cell exhaustion and improve their function,” said corresponding author Hongbo Chi, PhD, St. Jude Department of Immunology chair. “When we deleted Zmynd8, we saw improved CD8+ T-cell function against tumors and chronic infections, suggesting we may have a new therapeutic target to explore to improve these therapies.”
The protein ZMYND8 normally acts as a molecular brake on the expression of certain genes, such as that of the IL-2 receptor (Il2ra). The study shows that ZMYND8 can be co-opted by chronic viral infection and some cancers to turn off activation signals in CD8+ T cells. Removing the corresponding gene from CD8+ T cells improved control of chronic viral infection and melanoma in mouse models compared to controls. Still, the researchers found they could improve these results even more.
“What we’re really excited about is how the combination with immunotherapy enhanced treatment efficacy,” Chi said.
As ZMYND8 loss improved immune function, the scientists tested whether deleting the gene could work with established immunotherapy approaches. They combined Zmynd8 deletion in CD8+ T cells with immune checkpoint blockade (drugs that block cancer’s ability to hide from the immune system) or IL-2. In both cases, they observed an increase in functional cells, a decrease in exhausted cells and an even more profound increase in survival of mice receiving the combination treatments. The findings suggest that targeting ZMYND8 may be a strategy to overcome CD8+ T-cell exhaustion and improve immunotherapy.
Finding the source of T-cell exhaustion
To find out what regulates CD8+ T-cell exhaustion, the researchers examined the effects of removing genes involved in gene expression using single-cell CRISPR screening. “We found that ZMYND8 is a ‘master’ regulator of CD8+ T-cell exhaustion,” said co-first author Yan Wang, PhD, St. Jude Department of Immunology. “Its deletion enhanced effector cell formation, leading to the improved anti-tumor and anti-viral effects we observed.”
After identifying this master regulator, the team sought to understand how it controlled CD8+ T-cell fate. The researchers uncovered that ZMYND8 binds to and suppresses the activity of p300, which controls the transcriptional activation of the IL-2 receptor gene. This finding reveals the molecular link between overstimulation and CD8+ T-cell exhaustion.
“ZMYND8 can transform the chronic antigen stimulation signal that occurs in chronic viral infections and cancer into suppression of IL-2 receptor signaling, leading to an exhausted cell state,” said co-first author Hao Shi, PhD, St. Jude Department of Immunology.
With a clear map of how ZMYND8 leads to CD8+ T-cell exhaustion, researchers can explore how to enhance immunotherapy efficacy even more. “We have a new approach that could synergize with immunotherapy,” Chi said. “One day, a combination treatment approach could improve survival for patients with solid tumors.”
Authors and funding
The study’s other authors are Nicole Chapman, Anil KC, Renqiang Sun, and Hao Song, all of St. Jude, and Xiaoxi Meng and Xiang Sun, formerly of St. Jude.
The study was supported by grants from the National Institutes of Health (NIH) (CA253188, AI105887, AI131703, AI140761, AI150241 and AI150514), Cancer Center Support Grant (P30 CA021765) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.
St. Jude Children's Research Hospital
St. Jude Children’s Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. As the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children, St. Jude advances groundbreaking research and shares its discoveries worldwide to accelerate progress in pediatric medicine. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to more than 80% since the hospital opened more than 60 years ago. Through collaboration and innovation, St. Jude is working to ensure that children everywhere have access to the best possible care. To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.