PIKfyve controls dendritic cell function and tumor immunity II
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA986531 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24998200_1.fastq.gz | Fastqsanger.gz | |||
| SRR24998200_2.fastq.gz | Fastqsanger.gz | |||
| SRR24998201_1.fastq.gz | Fastqsanger.gz | |||
| SRR24998201_2.fastq.gz | Fastqsanger.gz | |||
| SRR24998202_1.fastq.gz | Fastqsanger.gz |
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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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Project description:PIKfyve controls dendritic cell function and tumor immunity I
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Project description: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.
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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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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.
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Project description:Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit primary resistance. Here, we found thatgenetic or pharmacologic inhibitionof the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis,upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, reduced tumor proliferation, and increased intratumoral functional CD8+T cellsinsyngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion was CD8+T cell- and MHC-I-dependent,as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to various immunotherapies, including immune checkpoint blockade (ICB), adoptive cell therapy, and therapeutic vaccines. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as novel agents to increase immunotherapy response in cancer patients.
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Project description:RNA sequencing analysis of human iPSC-derived motor neurons generated from two C9ORF72 ALS/FTD patient lines, treated with negative control ASO (NC ASO) or PIKFYVE ASO. The goal of this study is to evaluate the effect of PIKFYVE suppression in rescuing ALS motor neuron degeneration.
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Project description:While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease.
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