Using Expanded Natural Killer Cells as Therapy for Invasive Aspergillosis

Area of Science:

• Immunology
• Mycology
• Infectious Diseases

Background:

• Invasive aspergillosis (IA) poses a significant threat to immunocompromised patients, particularly those with hematological malignancies.
• High morbidity and mortality rates persist despite conventional antifungal therapies due to impaired host immune responses.
• Immunotherapy is being explored as a potential adjunctive treatment strategy for IA.

Purpose of the Study:

• To evaluate the efficacy of expanded human natural killer (NK) cells against Aspergillus fumigatus infection.
• To investigate the mechanisms underlying NK cell-mediated fungal killing.
• To assess the therapeutic potential of adoptive NK cell transfer in a preclinical model of IA.

Main Methods:

• Human NK cells were expanded and activated using genetically modified K562 feeder cells (K562-41BBL-mbIL-15).
• In vitro antifungal activity was assessed through fungal killing assays against Aspergillus fumigatus.
• In vivo efficacy was evaluated using an immunocompromised mouse model of pulmonary aspergillosis, employing adoptive NK cell transfer.

Main Results:

• Expanded NK cells demonstrated potent fungicidal activity against Aspergillus fumigatus, particularly targeting conidia, at a low effector-to-target ratio (2:1).
• NK cell-mediated killing was dependent on dectin-1 receptors, leading to enhanced perforin release and direct cytolysis.
• Adoptive transfer of expanded NK cells significantly reduced fungal burden in the pulmonary aspergillosis mouse model.

Conclusions:

• Expanded human NK cells exhibit significant in vitro and in vivo antifungal activity against Aspergillus fumigatus.
• The dectin-1 receptor pathway plays a crucial role in NK cell-mediated fungal clearance.
• Expanded NK cells represent a promising adjunctive immunotherapy for invasive aspergillosis in immunocompromised patients.