Researchers have identified key factors that determine the success of donor lymphocyte infusion (DLI) in patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic stem cell transplant. The study, published in Science Immunology, highlights the importance of a specific T cell population and the patient's bone marrow microenvironment in achieving remission.
Identifying Key Immune Cells
The research team, led by Elham Azizi from Columbia Engineering and Katie Maurer and Catherine Wu from Dana-Fararber Cancer Institute, analyzed bone marrow samples from 25 relapsed AML patients treated with stem cell transplant and DLI. Using single-cell sequencing, they discovered that patients responding to DLI had distinct cellular populations in their bone marrow compared to non-responders.
"The goal of our research is to identify the ways in which some patients respond, in the hopes that uncovering these mechanisms can help us create improved therapies that are more effective for a greater number of patients," said Maurer.
The study pinpointed a specific immune cell type, CD8+ cytotoxic T lymphocytes expressing the transcription factor ZNF683/Hobit, as crucial for the graft-versus-leukemia effect. These cells coordinate with other immune cells to expand and attack leukemia cells. In non-responding patients, these T cells showed lower ZNF683/Hobit expression and higher levels of inhibitory markers.
The Role of the Bone Marrow Microenvironment
The research also revealed that a healthier, more active, and diverse immune environment in the bone marrow supports the cancer-fighting abilities of these T cells. This suggests that the patient's immune environment plays a critical role in the success of DLI, potentially explaining why some patients benefit from immunotherapy while others do not.
"This research exemplifies the power of combining computational and experimental methods through close collaboration to answer complex biological questions and uncover unexpected insights," said Azizi.
Implications for Improved Immunotherapy
The findings suggest potential strategies for improving cancer immunotherapy, such as enhancing the immune environment before DLI treatment or exploring combinations of immunotherapies. This could lead to personalized treatment options for patients who do not typically respond well to DLI.
The team plans to further explore interventions that enhance DLI effectiveness by modulating the tumor microenvironment, with the ultimate goal of improving outcomes for patients with relapsed AML. Current DLI treatment has a 5-year survival rate of only 24% for relapsed AML patients.
