Human natural killer cells: origin, receptors, function, and clinical applications

Area of Science:

• Immunology
• Oncology
• Hematology

Background:

• Natural killer (NK) cells are vital components of innate immunity, involved in tumor surveillance and antiviral defense.
• NK cell function is regulated by inhibitory receptors (KIR, NKG2A) recognizing HLA class I and activating receptors sensing tumor/viral ligands.
• Tumor microenvironments can suppress endogenous NK cell anti-tumor activity.

Purpose of the Study:

• To elucidate the role of alloreactive NK cells in high-risk leukemia treatment.
• To highlight the contribution of KIR2DS1 to NK cell alloreactivity.
• To emphasize the clinical benefits of infusing mature alloreactive NK cells and TCRγδ(+) T cells in haplo-HSCT.

Main Methods:

• Analysis of NK cell recognition mechanisms involving HLA class I and KIR/NKG2A receptors.
• Investigation of NK cell activation pathways via activating receptors and their ligands.
• Assessment of alloreactive NK cell populations in haploidentical hematopoietic stem cell transplantation (HSC) for leukemia.

Main Results:

• Alloreactive NK cells derived from haploidentical donors are key in curing high-risk leukemia by targeting leukemia blasts and host dendritic cells.
• The HLA-C2-specific activating receptor KIR2DS1 can enhance NK cell alloreactivity in specific patient populations.
• A strong correlation exists between the size of the alloreactive NK cell population and favorable clinical outcomes.
• Direct infusion of donor-derived mature alloreactive NK cells and TCRγδ(+) T cells alongside HSC accelerates anti-leukemia effects and pathogen defense.

Conclusions:

• Alloreactive NK cells are critical for effective leukemia treatment and prevention of relapse and graft-versus-host disease.
• Enhancing haplo-HSCT with direct NK cell infusion offers a promising strategy for prompt anti-leukemia immunity.
• Targeting NK cell alloreactivity represents a significant advancement in immunotherapy for hematological malignancies.