PIKfyve, expressed by CD11c-positive cells, controls tumor immunity

• Published in: Nature communications Vol. 15; no. 1; pp. 5487 - 15
• Main Authors: Choi, Jae Eun, Qiao, Yuanyuan, Kryczek, Ilona, Yu, Jiali, Gurkan, Jonathan, Bao, Yi, Gondal, Mahnoor, Tien, Jean Ching-Yi, Maj, Tomasz, Yazdani, Sahr, Parolia, Abhijit, Xia, Houjun, Zhou, JiaJia, Wei, Shuang, Grove, Sara, Vatan, Linda, Lin, Heng, Li, Gaopeng, Zheng, Yang, Zhang, Yuping, Cao, Xuhong, Su, Fengyun, Wang, Rui, He, Tongchen, Cieslik, Marcin, Green, Michael D., Zou, Weiping, Chinnaiyan, Arul M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.06.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/21; 13/31; 38/39; 38/91; 631/250/2502; 631/250/2504/133; 631/250/516/1909; 64/60; 692/4028/67/580; Ablation; Animal models; Animals; Antigen presentation; Antigens; Cancer; Cancer immunotherapy; Cancer therapies; Cancer vaccines; CD11c antigen; CD11c Antigen - metabolism; CD8 antigen; Cell culture; Cell Line, Tumor; Clonal deletion; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Female; Gene expression; Humanities and Social Sciences; Humans; Hydrazones; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunity; Immunotherapy; Immunotherapy - methods; Kinases; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; Morpholines - pharmacology; multidisciplinary; Myeloid cells; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - therapy; NF-kappa B - metabolism; NF-κB protein; Phosphatidylinositol 3-Kinases - metabolism; Protein kinase inhibitors; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Pyrimidines; Science; Science (multidisciplinary); T-Lymphocytes - immunology; Tumors; Vaccines
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48931-9

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.