PIKfyve controls dendritic cell function and tumor immunity

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Cancer treatment increasingly utilizes immunotherapy and targeted therapies like protein kinase inhibitors.
• Mechanisms linking cancer-targeting drugs to dendritic cell (DC) mobilization and immunotherapy effectiveness remain unclear.

Purpose of the Study:

• To investigate the role of PIKFYVE gene expression in patient response to immune checkpoint blockade (ICB).
• To explore the impact of PIKfyve inhibition on DC function and anti-tumor immunity.

Main Methods:

• Analysis of PIKFYVE expression in relation to ICB response in cancer patients.
• Genetic ablation and pharmacological inhibition of PIKfyve in dendritic cells.
• Evaluation of tumor growth, T cell immunity, and ICB efficacy in preclinical mouse models.
• Assessment of apilimod (PIKfyve inhibitor) in combination with vaccine adjuvants.

Main Results:

• High PIKFYVE expression correlated with poorer complete response to ICB and reduced DC function.
• PIKfyve ablation in DCs enhanced their function through the non-canonical NF-κB pathway.
• PIKfyve inhibition (genetic or apilimod) suppressed tumor growth and improved DC-dependent T cell responses.
• Apilimod treatment potentiated ICB efficacy and, with a vaccine adjuvant, reduced tumor progression in vivo.

Conclusions:

• PIKfyve acts as a negative regulator of dendritic cell function.
• PIKfyve inhibition demonstrates significant potential for enhancing cancer immunotherapy and vaccine strategies.