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Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression [Nanostring]

ABSTRACT: Due to the limited efficacy of Immune checkpoint blockade (ICB) in mammary solid tumors alternative strategies are required. We demonstrated that cholesterol homeostasis plays a significant role in myeloid immune function and breast cancer progression. In this study, we focus on NR0B2. We conducted both in vitro and in vivo studies along with developing a small molecule agonist. NR0B2 functions within myeloid immune cells as a regulator of the NLRP3 inflammasome, which further facilitates T cell differentiation away from immune-suppressive regulatory T cells (Treg). Furthermore, this signaling pathway was demonstrated to attenuate breast tumor growth and metastasis in mouse models.

ORGANISM(S): Mus musculus

PROVIDER: GSE241917 | GEO | 2023/09/04

REPOSITORIES: GEO

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Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression [BMDM_RNA-Seq]

Project description:Due to the limited efficacy of Immune checkpoint blockade (ICB) in mammary solid tumors alternative strategies are required. We demonstrated that cholesterol homeostasis plays a significant role in myeloid immune function and breast cancer progression. In this study, we focus on NR0B2. We conducted both in vitro and in vivo studies along with developing a small molecule agonist. NR0B2 functions within myeloid immune cells as a regulator of the NLRP3 inflammasome, which further facilitates T cell differentiation away from immune-suppressive regulatory T cells (Treg). Furthermore, this signaling pathway was demonstrated to attenuate breast tumor growth and metastasis in mouse models.

2023-09-04 | GSE241916 | GEO

Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression [PyMT_RNA-Seq]

2023-09-04 | GSE241915 | GEO

Re-education of myeloid immune cells to reduce regulatory T cell expansion and impede breast cancer progression

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-09-04 | GSE241918 | GEO

Ablation of NLRP3 inflammasome rewires MDSC function and promotes tumor regression

Project description:Myeloid-derived suppressor cells (MDSCs) are myeloid precursors which exert potent immunosuppressive properties in cancer. Despite the extensive knowledge on mechanisms implicated in mobilization, recruitment and function of MDSCs, still their therapeutic targeting remains an unmet need in cancer immunotherapy suggesting that unappreciated mechanisms of MDSC-mediated suppression exist. Herein, we demonstrate an important role of NLRP3 inflammasome in the functional properties of MDSCs in tumor-bearing hosts. Specifically, Nlrp3-deficient mice exhibited reduced tumor growth compared to wild-type animals and induction of robust anti-tumor immunity, accompanied by re-wiring of the MDSC compartment. Interestingly, both monocytic (M-MDSCs) and granulocytic (G-MDSCs) subsets from Nlrp3-/- mice displayed impaired suppressive activity and demonstrated significant transcriptomic alterations supporting the loss-of-function and associated with metabolic re-programming. Finally, therapeutic targeting of NLRP3 inhibited tumor development and re-programmed the MDSC compartment. These findings propose that targeting NLRP3 in MDSCs could overcome tumor-induced tolerance and may provide new checkpoints of cancer immunotherapy.

2022-08-08 | GSE188973 | GEO

Nanoligomers targeting NF-κB and NLRP3 reduce neuroinflammation and improve cognitive function with aging and tauopathy

Project description:Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver of both age- and tau-associated neuroinflammation is the NF-κB and NLRP3 signaling axis. However, current treatments targeting NF-κB or NLRP3 may have adverse/systemic effects, and most have not been clinically translatable. Here, we tested the efficacy of a novel, nucleic acid therapeutic (Nanoligomer) cocktail specifically targeting both NF-κB and NLRP3 in the brain for reducing neuroinflammation and improving cognitive function in old wildtype mice, and in a mouse model of tauopathy. We found that 4 weeks of NF-κB/NLRP3-targeting Nanoligomer treatment strongly reduced neuro-inflammatory cytokine profiles in the brain and improved cognitive-behavioral function in both old and tauopathy mice. These effects of NF-κB/NLRP3-targeting Nanoligomer treatment were associated with reduced glial cell activation in old wildtype mice, less pathology in tauopathy mice, favorable changes in transcriptome signatures of inflammation (reduced) and neuronal health (increased) in both mouse models, and no adverse systemic effects. Collectively, our results provide a basis for future translational studies targeting NF-κB/NLRP3 in the brain, perhaps using Nanoligomers, to inhibit neuroinflammation and improve cognitive function with aging and neurodegenerative disease.

2024-02-07 | GSE251888 | GEO

Genome-wide CRISPR/Cas9 knockout screen for novel regulators of mechanical stress on NLRP3 inflammasome activation

Project description:Immune cells sense the microenvironment to fine-tune their inflammatory responses. Patients with cryopyrin associated periodic syndrome (CAPS), caused by mutations in the NLRP3 gene, present auto-inflammation and its manifestation is largely dependent on environmental cues. However, the underlying mechanisms are poorly understood. Here, we uncover that KCNN4, a calcium-activated potassium channel, links PIEZO-mediated mechanotransduction to NLRP3 inflammasome activation. Yoda1, a PIEZO1 agonist, lowers the threshold for NLRP3 inflammasome activation. PIEZO-mediated sensing of stiffness and shear stress increases NLRP3-dependent inflammation. Myeloid-specific deletion of PIEZO1/2 protects mice from gouty arthritis. Activation of PIEZO1 triggers calcium influx, which activates KCNN4 to evoke potassium efflux promoting NLRP3 inflammasome activation. Activation of PIEZO signaling is sufficient to activate the inflammasome in cells expressing CAPS-causing NLRP3 mutants via KCNN4. Finally, pharmacologic inhibition of KCNN4 alleviates auto-inflammation in CAPS patient cells and in CAPS-mimicking mice. Thus, PIEZO-dependent mechanical inputs augment inflammation in NLRP3-dependent diseases including CAPS.

2023-10-26 | GSE246208 | GEO

Western diet triggers NLRP3-dependent persistent functional reprogramming of myeloid cells [ATAC-Seq]

Project description:Here we investigated whether sterile triggers of inflammation induce trained immunity and thereby influence innate immune responses. Western diet (WD) feeding of Ldlr-/- mice induced systemic inflammation, which was undectable in serum soon after mice were shifted back to chow diet (CD). In contrast, myeloid cell responses towards innate stimuli remained broadly augmented. WD induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells, leading to increased proliferation as well as enhanced innate immune and interferon responses towards in vivo LPS challenge. QTL analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with LPS suggested inflammasome-mediated trained immunity. Consistently, Nlrp3-/-/Ldlr-/--deficient mice lacked WD-induced systemic inflammation or myeloid progenitor proliferation and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby arbitrate the potentially deleterious effects of trained immunity in inflammatory diseases.

2018-01-17 | GSE97924 | GEO

Western diet triggers NLRP3-dependent persistent functional reprogramming of myeloid cells [RNA-Seq]

2018-01-17 | GSE97925 | GEO

Western diet triggers NLRP3-dependent persistent functional reprogramming of myeloid cells II [RNA-Seq]

2018-01-17 | GSE106789 | GEO

NanoString- Transcriptional profiling of LPS-primed and inflammasome-activated untouched, or platelet-depleted human CD14+ monocytes

Project description:The goal of this experiment was to explore how human platelets affect the transcriptional responses of primary human CD14+ blood monocytes to lipopolysaccharide (LPS), and NLRP3 activation with Nigericin. For this purpose, we analyzed the mRNA expression of 770 myeloid-specific transcripts using the nCounter® Nanostring Human Myeloid Innate Immunity Panel v2. We isolated classical monocytes (CD14+CD16−) from the peripheral blood of healthy volunteers. Monocytes were derived from PBMCs using negative selection with the EasySep™ Human Monocyte Isolation Kit from STEMCELLTM Technologies. We modified this process by either including or excluding a platelet-depleting cocktail, creating two groups: \\"Standard Monocytes (StdMo)\\" and \\"Platelet-depleted Monocytes (PdMo).\\" To examine the impact of platelets further, we supplemented PdMos with fresh autologous platelets at a ratio of 50 platelets per monocyte, resulting in a third group, \\"PdMo + Plts.\\" StdMos were prepared according to the standard protocol provided by the EasySep™ Kit. For the PdMos, a Platelet Removal Component (50 µl ml−1) from the kit was used during isolation. We also reconstituted platelet-depleted monocytes with platelets and analyzed platelets alone to determine their specific mRNA contributions. The groups—StdMo, PdMo, PdMo + Plts, and platelets alone—were then exposed to 2 ng/ml of Ultrapure LPS (from E. coli O111:B4) for 4.5 hours, or stimulated with LPS for 3 hours followed by inflammasome activation with Nigericin (10 µM) for 90 min before extracting RNA for analysis.

2024-05-31 | E-MTAB-14072 | biostudies-arrayexpress

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