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Autophagy Inhibition via Targeting of PIKfyve Potentiates Immune Checkpoint Blockade in Prostate Cancer Therapy

ABSTRACT: To understand the tumor microenvironment changes in terms of transcriptome upon PIKfyve inhibition by small molecule ESK981 and the immune checkpoint inhibitor anti-PD-1 in Myc-CaP syngeneic mouse model.

ORGANISM(S): Mus musculus

PROVIDER: GSE174644 | GEO | 2021/05/18

REPOSITORIES: GEO

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Autophagy Inhibition via Targeting of PIKfyve Potentiates Immune Checkpoint Blockade in Prostate Cancer Therapy

Project description:Autophagy Inhibition via Targeting of PIKfyve Potentiates Immune Checkpoint Blockade in Prostate Cancer Therapy

| PRJNA730874 | ENA

Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer.

Project description: Not available

| S-EPMC8562569 | biostudies-literature

PIKfyve inhibition upregulates surface expression of MHC class I to enhance immune responses in cancer

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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Alveolar macrophage gene expression - PIKfyve knockout

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

2017-03-01 | GSE93849 | GEO

Protease dysregulation during response and resistance to immune checkpoint blockade therapy (RNA-seq)

Project description:Immune checkpoint blockade (ICB) therapy does not benefit the majority of treated patients, and those who respond to the therapy can become resistant to it. Here we report the design and performance of systemically administered activity sensors conjugated to anti-programmed cell death protein 1 (αPD1) antibodies for the monitoring of antitumour responses to ICB therapy. RNA sequencing analysis revealed that differential expression of tumour and immune proteases underpins ICB response and resistance. We then designed a library of mass-barcoded sensors that, when cleaved by proteases, are released into urine, where they can be detected by mass spectrometry. By using syngeneic mouse models of colorectal cancer, we show that random-forest classification trained on mass-spectrometry signatures can be used to detect early antitumour responses and to discriminate resistance to ICB therapy driven by loss-of-function mutations in either the B2m or Jak1 genes. Our data supports the use of activity-based biomarkers that leverage protease dysregulation for response assessment and classification of refractory tumours.

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Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer.

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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

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.

2023-06-26 | GSE235599 | GEO

PIKfyve controls dendritic cell function and tumor immunity I

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.

2023-06-26 | GSE235596 | GEO

PIKFYVE Inhibition Mitigates Disease in Models of Diverse Forms of ALS [2]

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.

2022-12-18 | GSE221016 | GEO

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