Immunotherapy, using a patient’s own immune system to treat disease, has shown promise in some patients with cancer but has not worked in most.

New research from St. Jude Children’s Research Hospital and colleagues found that disrupting Asxl1, a gene in T cells, improved sensitivity to a type of immunotherapy called immune checkpoint blockade and improved long-term tumour control in modes systems.

The findings were published in Science.

Cells of the immune system use “checkpoints” or signals that tell them how to react to diseased cells or pathogens.

Tumours can hijack these checkpoints to turn the immune system off, helping the cancer cells hide and survive.

Immune checkpoint inhibitors or blockades can stop tumours’ 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 tumour 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-tumour response.”

To make this finding required expertise in both immune cell signalling 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 tumours, 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.

Source: St. Jude Children's Research Hospital