Targeting leukemic stem cell biomechanics suppresses stemness and enhances NK cell-mediated immunotherapy

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Immunology

Background:

• Acute myeloid leukemia (AML) is driven by leukemic stem cells (LSCs), which cause relapse and resistance to therapy.
• The mechanical properties of LSCs are largely unexplored, yet crucial for understanding their behavior and developing new treatments.

Purpose of the Study:

• To investigate the mechanical properties of LSCs and their role in AML.
• To explore novel therapeutic strategies targeting LSC mechanical characteristics and enhancing immunotherapy.

Main Methods:

• Utilized microfluidic chips for selective isolation of LSCs based on mechanical properties.
• Performed single-cell RNA-sequencing on primary human AML bone marrow to identify LSC subpopulations.
• Investigated the effects of ALDH1A1 inhibition on LSC stiffness, stemness, and susceptibility to natural killer (NK) cell cytotoxicity.
• Evaluated the combination of ALDH1A1 inhibition and NK cell therapy in AML patient-derived xenograft models.

Main Results:

• Discovered that LSCs are predominantly small and mechanically soft, allowing for their isolation using microfluidic chips.
• Identified the FSC^low ALDH1A1⁺ subpopulation as enriched in LSCs with long-term stemness.
• ALDH1A1 inhibition increased LSC stiffness and reduced stemness, enhancing NK cell-mediated cytotoxicity.
• Combined ALDH1A1 inhibition with NK cell therapy significantly suppressed leukemia progression in xenograft models.

Conclusions:

• Targeting the mechanical properties of LSCs presents a promising strategy to overcome AML treatment resistance.
• ALDH1A1 inhibition can modulate LSC mechanics, making them more vulnerable to immunotherapy.
• Combining targeted therapies with immunotherapy offers a potential approach to improve clinical outcomes in AML.