Researchers at St. Jude Children’s Research Hospital and their collaborators have discovered that targeting the Asxl1 gene in T cells can enhance the sensitivity of patients to immune checkpoint blockade (ICB) therapy and boosts long-term tumor control. The findings, published in the journal Science, suggest a promising new method to improving treatment outcomes in patients receiving ICB therapy.
ICB has shown success treating some forms of cancer such as melanoma, lung cancer, and bladder cancer. According to the American Cancer Society, these therapies have improved survival rates for some patients, with efficacy rates ranging from 20–40% depending on the specific cancer type and patient population. However, the majority of patients do not respond to this form of immunotherapy.
The research was spurred by a desire to better understand why some people respond to ICB therapy and others don’t, as well as what influences CD8 T cells to become exhausted and stop fighting cancer after a period of sustained stimulation by immunotherapies. To attempt to unravel these factors, the St. Jude team dug into the genetics of patients who did respond to ICB therapy.
ASXL1 Mutation and Improved Survival
For their research, the investigators examined a small cohort of patients with myelodysplastic syndrome (MDS) who demonstrated improved long-term survival after receiving an anti-PD-L1 therapy. “We found Asxl1 mutated in the T cells of all of those patients and decided to investigate further,” said senior author Caitlin Zebley, MD, PhD, from the department of bone marrow transplantation and cellular therapy at St. Jude.
Following this finding, the team then knocked out Asxl1 in the T cells of mouse models and found that during checkpoint blockade, the immune system in these mice controlled tumors better and for a long period of time compared with mice who still had Asxl1. This yielded the finding that Asxl1 operates within an epigenetic framework, influencing the differentiation process of T cells.
Epigenetic Control of T Cell Exhaustion
Specifically, it acts as a regulator of the polycomb group-repressive deubiquitinase (PR-DUB) complex, which plays a role in maintaining T cell function and preventing their transition to an exhausted state. The effects of this preservation were maintained over the course of a year, potentially improving the effectiveness of ICBs to provide a longer-term treatment option.
“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, of St. Jude’s 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.”
Data for patients that had received ICB treatments used in the study was provided by the Van Andel Institute-Stand Up To Cancer Epigenetic Dream Team. “Immunotherapies have saved countless lives, noted Peter A. Jones, PhD, president and chief scientific officer of the Van Andel Institute. “Today’s findings demonstrate how epigenetics can further improve these powerful treatments to help even more people.”
