Recent studies at St. Jude Children’s Research Hospital and collaborators have provided insights suggesting that alterations in the Asxl1 gene within T cells play a significant role in enhancing the effectiveness of immunotherapies, specifically immune checkpoint blockade, which helps achieve improved long-term control of tumors in experimental models. These findings were published today in Science.
Immune cells utilize “checkpoints,” which are signals guiding their responses to diseased cells or infections. However, tumors can exploit these checkpoints to deactivate the immune system, allowing cancer cells to evade detection and thrive. Immune checkpoint inhibitors work by obstructing these suppressive actions of tumors, thereby enabling the immune system to recognize and destroy cancer cells.
“Our research indicates that knocking out the Asxl1 gene in T cells led to a significantly improved response to immune checkpoint therapy,” stated Caitlin Zebley, MD, PhD, one of the senior authors from St. Jude Department of Bone Marrow Transplantation and Cellular Therapy.
When T cells encounter excessive fragments of tumor cells, they can become “exhausted,” diminishing their ability to eliminate cancer cells. The researchers discovered that the deletion of Asxl1 prevented this exhaustion in T cells, supporting sustained immune responses.
“We’ve identified that Asxl1 regulates an epigenetic checkpoint that maintains T cells in a state of terminal differentiation leading to exhaustion. Once T cells pass this checkpoint, they become ineffective in immunotherapy,” explained Ben Youngblood, PhD, co-corresponding author from St. Jude Department of Immunology. “This molecular checkpoint finding is crucial because it opens pathways to enhance T cells for a lasting anti-tumor response.”
This discovery required significant expertise in immune cell signaling and immunotherapy, coupled with patient samples from those who effectively underwent treatment with immune checkpoint blockade, emphasizing the value of collaborative efforts in scientific research.
“Immunotherapies have saved numerous lives, and our latest results demonstrate the potential of epigenetics to enhance these powerful treatments, benefiting even more patients,” remarked co-author Peter A. Jones, PhD, D.Sc. (hon), president and chief scientific officer at the Van Andel Institute and a leader of the Van Andel Institute-Stand Up To Cancer® Epigenetics Dream Team, which provided patient data. “We are excited to support this vital research, highlighting the power of collaboration in our fight against cancer.”
Reverse engineering immunotherapy success
Immune checkpoint blockade has proven effective and occasionally curative for a select group of cancer patients, a discovery that was honored with the 2018 Nobel Prize in Physiology or Medicine awarded to James P. Allison and Tasuku Honjo. Despite its success, this method remains ineffective for many patients. Therefore, Youngblood, Zebley, and their research team analyzed the genetics of those who responded to identify differences in their biological makeup.
“We conducted a study on a limited group of patients with myelodysplastic syndrome who demonstrated significant improvement in long-term survival following treatment with a specific checkpoint inhibitor,” said Zebley. “In all these patients, we found mutations in ASXL1 within their T cells, prompting us to explore further.”
The researchers proceeded to remove Asxl1 from T cells in mice. They discovered that these modified mice showed enhanced immune responses and better tumor control during checkpoint blockade compared to mice with intact Asxl1. Further analysis revealed that disrupting the Asxl1 gene helped preserve a subset of T cells that remained functional and capable of maintaining their cancer-fighting abilities for more than a year.
“Our findings indicate that Asxl1 disruption grants T cells exceptional long-term therapeutic ability, suggesting a promising direction for developing future T cell-based immunotherapy,” stated Zebley.
Authors and funding
The lead author of this study is Tae Gun Kang from St. Jude. Other contributors include Xin Lan, Tian Mi, Hongfeng Chen, Shanta Alli, Anoop Babu Vasandan, Grace Ward, Peter Vogel, and Christopher Derenzo from St. Jude; Song-Eun Lim, Sheetal Bhatara, Jiyang Yu, and Xin Lan from the University of Tennessee Health Science Center; Sofia Bentivegna, Jakob Schmidt Jespersen, Kirsten Grønbæk, and Balthasar Clemens Schlotmann from Copenhagen University Hospital; Josh Jang from Van Andel Institute-Stand Up To Cancer®; Marianne Spatz and Jin-Hwan Han from Merck & Co. Inc.; Stephen Baylin from The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Casey O’Connell from the University of Southern California; and Kirsten Grønbæk from the University of Copenhagen.
The research received funding from grants from the National Institutes of Health (R01AI114442, R01CA237311, K08CA279926-0, and R35CA209859), the National Comprehensive Cancer Network Young Investigator Award, the Alex Lemonade Stand Young Investigator Grant, the Van Andel Research Institute — Stand Up To Cancer® Epigenetics Dream Team (part of the Entertainment Industry Foundation), the ASSISI Foundation, Merck & Co., and ALSAC, the fundraising and awareness organization for St. Jude.
