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PIKfyve controls dendritic cell function and tumor immunity I

ABSTRACT: To understand the mechanism of Pikfyve loss in dendritic cells, we cultured conventional dendritic cells isolated from the bone marrow of Pikfyvef/f (“WT”) and mice with ItgaxTg/0 Pikfyvef/f (“KO”) mice and performed transcriptome profiling on RNA extracted from cells on Day 9 in culture. Taken together, these data demonstrate the PIKfyve mediates suppression of DC transcriptional maturation programs through the alternate/non-canonical NF-κB regulatory pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE235596 | GEO | 2023/06/26

REPOSITORIES: GEO

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PIKfyve controls dendritic cell function and tumor immunity II

Project description:To understand the mechanism of Pikfyve inhibition in dendritic cells, we cultured conventional dendritic cells isolated from the bone marrow of wild-type mice and performed transcriptome profiling on RNA extracted from cells treated with DMSO or apilimod for 3 or 8 hours on Day 6 in culture. Taken together, these data demonstrate the PIKfyve mediates suppression of DC transcriptional maturation programs through the alternate/non-canonical NF-κB regulatory pathway.

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PIKfyve controls dendritic cell function and tumor immunity I

Project description:PIKfyve controls dendritic cell function and tumor immunity I

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PIKfyve controls dendritic cell function and tumor immunity II

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PIKfyve controls dendritic cell function and tumor immunity.

Project description:The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs 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 controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

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Project description:comparison of Alveolar macrophge gene expression in wild type and PIKfyve ko We identifed gene that important for alveolar macrophage development

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IFN lambda modulates dendritic cells to facilitate T cell immunity during influenza virus infection

Project description:Type I and type III interferon (IFN) are important in regulating responses to viral infection. Type I IFN signaling is know to contribute to dendritic cell (DC) function, but the contribution of type III IFN remains unknown. To determine changes in migratory dendritic cell gene expression during influenza A virus (IAV) in the presence or absence of type I or type III (IFN) receptors, C57Bl/6 (WT) mice, mice lacking the type I IFN receptor (Ifnar-/-), and mice lacking the type III IFN receptor (Ifnlr-/-) were infected intranasally with 40 plaque forming units (PFU) IAV H1N1 strain A/PR/8/34 or mock infected. On day 4, lung-draining lymph nodes (dLN) were harvested, conventional DC were isolated, and mRNA sequencing (mRNAseq) was performed.

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Identification of PIKfyve kinase as a target in multiple myeloma

Project description:The cellular cytotoxicity of APY0201, a PIKfyve inhibitor, against multiple myeloma was initially identified in an unbiased in vitro chemical library screen. Activity was confirmed in all 25 cell lines tested and 40% of 100 ex vivo patient derived primary samples, and positively correlated with samples harboring trisomies and inversely related to t(11;14). The broad anti- multiple myeloma activity of PIKfyve inhibitors was further demonstrated in confirmatory screens and showed the superior potency of APY0201 when compared to the PIKfyve inhibitors YM201636 and apilimod, with a mid-point EC50 at nanomolar concentrations respectively in 65%, 40%, and 5% of the tested cell lines. An up-regulation of genes in the lysosomal pathway and increased cellular vacuolization was observed in vitro in cell lines following APY0201 treatment however this cellular response did not correlate well with responsiveness. We confirm that PIKfyve inhibition is associated with activation of the transcription factor EB, a master regulator of lysosomal biogenesis and autophagy. Furthermore, we established an assay measuring autophagy as a predictive marker of APY0201 sensitivity. Overall, these findings suggest promising activity of PIKfyve inhibitors secondary to disruption of autophagy in multiple myeloma and a strategy to enrich for likely responders.

2019-09-19 | GSE134598 | GEO

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