Scientists Discover How Leukemia Cells Trick the Immune System

A team from Lund University has identified a mechanism that enables acute myeloid leukemia (AML) cells to avoid detection by the immune system. The mechanism involves a surface protein found exclusively on leukemia stem cells, not healthy blood cells, which the researchers targeted using a novel antibody.

The findings are reported in Nature Cancer.

A surface marker specific to leukemia stem cells

AML is an aggressive form of blood cancer with a five-year survival rate slightly above 30%. Standard treatments often involve chemotherapy and stem cell transplantation, yet many patients relapse due to the persistence of leukemia stem cells. These cells can survive treatment and are believed to drive the disease’s return.

The research team began by conducting a large-scale analysis of surface proteins in bone marrow samples from three individuals with difficult-to-treat AML. These were compared to samples from healthy donors.

“We wanted to see if we could find surface proteins unique to leukemia stem cells, and which would therefore act as interesting targets for a targeted treatment. If such proteins were not present on healthy blood stem cells it might be possible to attack the tumour – without harming the healthy blood system,” said Thoas Fioretos, research group leader and professor of clinical genetics at Lund University, and senior consultant at Skåne University Hospital.

The investigation identified a previously uncharacterised surface protein, SLAMF6, which was only found on the leukemia stem cells and not on healthy blood-forming stem cells. The finding was later confirmed in samples from 50 additional AML patients.

Blocking the immune evasion pathway

The role of SLAMF6 in immune evasion was examined using CRISPR/Cas9 gene-editing tools. The protein was found to suppress the activity of T cells, which are responsible for identifying and eliminating cancerous or infected cells. In the presence of SLAMF6, T cells failed to detect the leukemia cells, allowing them to proliferate.

To counter this, the team developed an antibody that binds to SLAMF6 and prevents it from interfering with the immune response. When tested on human cells transplanted into mice, the antibody restored T cell activity. In these in vivo models, the treated immune cells were able to detect and destroy leukemia cells.

“When we blocked the surface protein, using a specific antibody we developed in cooperation with the SciLifeLab Drug Discovery and Development Platform, the T cells could suddenly detect and kill the cancer cells – both in test tubes and in mice,” added Carl Sandén, researcher at Lund University.

Implications for immunotherapy in AML

Although immunotherapies have improved treatment outcomes in several cancers, they have shown limited success in AML. This study offers insight into why that might be the case. The presence of SLAMF6 on leukemia stem cells suggests the disease may use this protein as a defence mechanism to resist immune surveillance.

“Our discovery can partially explain why immunotherapies have thus far only had a limited effects in AML. It’s an important step forward, but continued research and clinical trials will be needed before it can be relevant as a treatment for a patient group that is in great need of new therapies,” said Niklas Landberg, research group leader at Lund University and medical registrar in hematology at Skåne University Hospital, and one of the researchers behind the study.

The researchers propose that therapies targeting SLAMF6 could complement existing treatment approaches. However, further development and testing of the antibody are required before it can be evaluated in clinical trials. The team has initiated this process through a spin-off company, Lead Biologics, which is advancing the antibody for potential therapeutic use.

Reference: Sandén C, Landberg N, Peña-Martínez P, et al. Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia. Nat Cancer. 2025. doi: 10.1038/s43018-025-01054-6

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