Disrupting Asxl1 gene prevents T-cell exhaustion, improving immunotherapy

Cells of the immune system use "checkpoints" or signals that tell them how to react to diseased cells or pathogens. Tumors can hijack these checkpoints to turn the immune system off, helping the cancer cells hide and survive. Immune checkpoint inhibitors or blockades can stop tumors' suppressive effects, helping the immune system find and kill cancer cells.

"We discovered that disrupting the Axsl1 gene in T cells resulted in a better response to immune checkpoint blockade," said senior co-corresponding author Caitlin Zebley, MD, PhD, St. Jude Department of Bone Marrow Transplantation and Cellular Therapy.

T cells that encounter too many tumor cell pieces can also become exhausted and lose their ability to kill cancerous cells. The researchers showed that removing Asxl1 prevented T-cell exhaustion, enabling long-term immune responses.

"We found Asxl1 controls the epigenetic checkpoint that reinforces the terminal differentiation of T cells into the exhausted state. When the T cells differentiate past this checkpoint, they are rendered essentially useless for immunotherapy," said co-corresponding author Ben Youngblood, PhD, St. Jude Department of Immunology. "Our discovery of this molecular checkpoint is a critical advancement for the field because it now allows us to further engineer T cells with a durable anti-tumor response."

To make this finding required expertise in both immune cell signaling and immunotherapy, as well as samples from patients who had been successfully treated with immune checkpoint blockade, highlighting the importance of collaboration in scientific research.

"Immunotherapies have saved countless lives. Today's findings demonstrate how epigenetics can further improve these powerful treatments to help even more people," said co-author Peter A. Jones, PhD, D.Sc. (hon), Van Andel Institute president and chief scientific officer and Van Andel Institute-Stand Up To Cancer® Epigenetics Dream Team co-leader, which provided data on patients that had received immunotherapy. "We are thrilled to support this vital work, which underscores the immense power of collaboration as we tackle cancer together."

Reverse engineering immunotherapy success

Immune checkpoint blockade has been highly effective and sometimes curative in a subset of cancer patients, with its discovery earning James P. Allison and Tasuku Honjo the 2018 Nobel Prize in Physiology or Medicine. But the approach does not work for all patients. Youngblood, Zebley, and their colleagues, therefore, examined the genetics of responders to figure out what is different about the biology of individuals who respond to immune checkpoint blockade.

"We looked at a small cohort of patients with myelodysplastic syndrome who had significantly improved long-term survival after treatment with a specific checkpoint inhibitor," Zebley said. "We found ASXL1 mutated in the T cells of all of those patients and decided to investigate further."

The researchers followed up by removing Asxl1 in mouse T cells. They found that during checkpoint blockade, the immune system in these mice was better able to control tumors, and for longer, compared to mice with Asxl1 intact. Further investigation revealed removing Asxl1 improved therapy by preserving a small group of T cells that avoided exhaustion and maintained their anticancer effect over a year.

"We showed Asxl1 disruption endows T cells with superior long-term therapeutic potential, which could be a promising strategy for the design of future T cell-based immunotherapies," Zebley said.

Authors and funding

The study's first author is Tae Gun Kang, of St. Jude. The study's other authors are Xin Lan, Tian Mi, Hongfeng Chen, Shanta Alli, Anoop Babu Vasandan, Grace Ward, Peter Vogel and Christopher Derenzo; St. Jude; Song-Eun Lim, Sheetal Bhatara, Jiyang Yu and Xin Lan; University of Tennessee Health Science Center; Sofia Bentivegna, Jakob Schmidt Jespersen, Kirsten Grønbæk and Balthasar Clemens Schlotmann; Copenhagen University Hospital; Josh Jang; Van Andel Institute-Stand Up To Cancer®; Marianne Spatz and Jin-Hwan Han; Merck & Co. Inc.; Stephen Baylin; The Sidney Kimmel Comprehensive Cancer Institute at Johns Hopkins; Casey O'Connell; University of Southern California and Kirsten Grønbæk; University of Copenhagen.

The study was supported by grants from the National Institutes of Health (R01AI114442 and R01CA237311, K08CA279926-0 and R35CA209859), the National Comprehensive Cancer Network Young

Investigator Award, Alex Lemonade Stand Young Investigator Grant, Van Andel Research Institute -- Stand Up To Cancer® Epigenetics Dream Team (Stand Up To Cancer is a division of the Entertainment Industry Foundation), ASSISI Foundation, Merck & Co. and ALSAC, the fundraising and awareness organization of St. Jude.