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PIKfyve, expressed by CD11c-positive cells, controls tumor immunity
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PIKfyve, expressed by CD11c-positive cells, controls tumor immunity
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Journal Article
PIKfyve, expressed by CD11c-positive cells, controls tumor immunity
2024
Overview
Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that
PIKFYVE
is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c
+
cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of
Pikfyve
in CD11c
+
cells and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively regulates the function of CD11c
+
cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.
Myeloid cell subsets are playing important roles in antitumour immunity, and genes affecting their functions are potential targets for immunotherapy. Here authors show that genomic deletion of Pikfyve in CD11c
+
cells results in tumour growth inhibition via enhanced antigen presentation and priming of antigen-specific CD8
+
T cells in a mouse tumor model.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/21
/ 13/31
/ 38/39
/ 38/91
/ 64/60
/ Ablation
/ Animals
/ Antigens
/ Cancer
/ Dendritic Cells - drug effects
/ Dendritic Cells - immunology
/ Dendritic Cells - metabolism
/ Female
/ Humanities and Social Sciences
/ Humans
/ Immune checkpoint inhibitors
/ Immune Checkpoint Inhibitors - pharmacology
/ Immune Checkpoint Inhibitors - therapeutic use
/ Immunity
/ Kinases
/ Male
/ Mice
/ Phosphatidylinositol 3-Kinases - metabolism
/ Protein Kinase Inhibitors - pharmacology
/ Protein Kinase Inhibitors - therapeutic use
/ Proteins
/ Science
/ Tumors
/ Vaccines
