Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner

ABSTRACT: Considering age is the greatest risk factor for many neurodegenerative diseases, aging, in particular aging of the immune system, is the most underappreciated and understudied contributing factor in the neurodegeneration field. Genetic variation around the LRRK2 gene affects risk of both familial and sporadic Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) protein has been implicated in peripheral immune signaling, however, the effects of an aging immune system on LRRK2 function have been neglected to be considered. We demonstrate here that the R1441C mutation induces a hyper-responsive phenotype in macrophages from young female mice, characterized by increased effector functions, including stimulation-dependent antigen presentation, cytokine release, phagocytosis, and lysosomal function. This is followed by age-acquired immune cell exhaustion in a Lrrk2-kinase-dependent manner. Immune-exhausted macrophages exhibit suppressed antigen presentation and hypophagocytosis, which is also demonstrated in myeloid cells from R1441C and Y1699C-PD patients. Our novel findings that LRRK2 mutations confer immunological advantage at a young age but may predispose the carrier to age-acquired immune exhaustion have significant implications for LRRK2 biology and therapeutic development. Indeed, LRRK2 has become an appealing target in PD, but our findings suggest that more research is required to understand the cell-type specific consequences and optimal timing of LRRK2-targeting therapeutics.

ORGANISM(S): Mus musculus

PROVIDER: GSE246691 | GEO | 2024/01/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer

Project description:<p>Mechanisms of acquired resistance to immune checkpoint inhibitors (ICIs) are poorly understood. The purpose of this study was to investigate whether alterations in genes encoding components of the HLA Class I antigen processing and presentation machinery or interferon signaling pathways play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Whole exome sequencing was performed on tumor samples collected from patients with advanced non-small cell lung cancer at the time of resistance to PD-1 axis inhibitors and on available matched pre-treatment and normal samples. Patient-derived xenografts successfully established from the ICI-resistant samples were also exome sequenced. Additionally, RNA sequencing was performed on cases with sufficient tissue.</p>

| phs001464 | dbGaP

Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation [WGBS]

Project description:The immune system undergoes a progressive functional remodeling with age, polarizing the immune responses toward a “killer” or “healer” phenotype. Understanding how the age bias shapes anti-tumor immunity is essential in designing effective immunotherapies. In this manuscript we explore the anti-tumor CD8+ T cell responses generated in young (prepubescent) and adult (pre-senescent) mice. Using an MHCI-deficient, trackable tumor model, we observed that tumor reactive CD8+ T cells that expanded in young tumor-bearing (TB) mice acquired a terminally differentiated phenotype characterized by overexpression of inhibitory receptors and the transcription factor Tox1. Furthermore, tumor infiltrating CD8+ T cells from young tumors yielded a poor cytokine response compared to CD8+ T cells infiltrating adult tumors. Young migratory dendritic cells (migDC) and mononuclear phagocytic cells (MPCs) infiltrating young tumors were more competent in capturing and cross-presenting tumor antigen, leading to enhanced priming of CD8+ T cells in the draining lymph nodes (dLNs), and their subsequent terminal differentiation in the tumors. Notably, single-cell transcriptional profiling of tumor infiltrating MPCs revealed that young MPCs are polarized toward an inflammatory, effector phenotype. Consistent with our observations in young vs adult TB mice, analysis of immune infiltrates from pediatric solid tumors revealed a significant correlation between tumor-infiltrating CD8+ T cells with an exhaustion phenotype and the frequency of PD-L1-expressing phagocytic cells. Collectively, these data indicate that the young microenvironment of an actively developing tissue contributes to the generation of an immune response skewed toward a terminal effector state, thus narrowing the window for immunotherapeutic interventions.

2022-02-28 | GSE188388 | GEO

Antigen cross-presentation in young tumor-bearing hosts promotes CD8 T cell terminal differentiation [gene expression]

2022-02-28 | GSE188387 | GEO

Clinical and molecular features of acquired resistance to immunotherapy [ATAC-seq]

Project description:Although immunotherapy with PD-(L)1 blockade is routine for lung cancer, little is known about acquired resistance. Among 1,201 patients with non-small cell lung cancer (NSCLC) treated with PD-(L)1 blockade, acquired resistance is common, occurring in >60% of initial responders. Acquired resistance shows differential expression of inflammation and interferon (IFN) signaling. Relapsed tumors can be separated by upregulated or stable expression of IFNγ response genes. Upregulation of IFNγ response genes is associated with putative routes of resistance characterized by signatures of persistent IFN signaling, immune dysfunction, and mutations in antigen presentation genes which can be recapitulated in multiple murine models of acquired resistance to PD-(L)1 blockade after in vitro IFNγ treatment. Acquired resistance to PD-(L)1 blockade in NSCLC is associated with an ongoing, but altered IFN response. The persistently inflamed, rather than excluded or deserted, tumor microenvironment of acquired resistance informs therapeutic strategies to effectively reprogram and reverse acquired resistance.

2024-01-11 | GSE249001 | GEO

Clinical and molecular features of acquired resistance to immunotherapy [RNA-seq]

2024-01-11 | GSE249000 | GEO

Clinical and molecular features of acquired resistance to immunotherapy in non-small cell lung cancer

2024-01-11 | GSE248249 | GEO

Transcriptomic analysis of cardiac gene expression associated to RAGE deletion and aging

Project description:Cardiac aging is characterized by increased cardiomyocyte hypertrophy, myocardial stiffness and fibrosis, which enhance the cardiovascular risk. The receptor for advanced glycation end-products (RAGE) is involved in several age-related diseases. Rage knockout (Rage-/-) mice show an acceleration of cardiac dimensions changes and interstitial fibrosis with aging. This study identifies the age-associated cardiac gene expression signature induced by RAGE deletion. We analyzed the left ventricle transcriptome of 2.5- (Young), 12- (Middle age, MA) and 21- (Old) month-old female Rage-/- and C57BL/6 (WT) mice. By comparing Young, MA and Old Rage-/- versus age-matched WT mice, we identified 122, 192 and 11 differently expressed genes, respectively. Functional inference analysis showed that RAGE deletion is associated with: (i) a down-regulation of genes involved in antigen processing and presentation of exogenous antigen, adaptive immune response, cytokine and type I- and gamma-interferon mediated pathway in Young animals; (ii) an up-regulation of genes related to fatty acid oxidation, cardiac structure remodeling and impaired response to hypoxia in MA mice; (iii) an up-regulation of few genes belonging to complement activation and triglyceride biosynthetic process in Old animals. Our findings show that the age-dependent cardiac phenotype of Rage-/- mice is mainly associated to alterations of genes related to adaptive immunity and cardiac stress pathways.

2022-10-01 | GSE210192 | GEO

Characterization of human aging and Parkinson’s disease pre-frontal cortex by multi-omics: a glycomics, proteomics study.

Project description:This study identifies the age and PD related changes in glycans (HS and CS disaccharides) and proteomics in human aging and Parkinson’s disease. We analyzed the prefrontal cortex for changes in HS, CS and proteomic signatures in young versus aged as well as aged and PD in two cohorts. These studies provide insight into age- and PD changes in glycans and proteomics. We assess changes with PD and observe for pathways that may correlate with transcriptomics. We also observe in aging related proteomic changes and transcriptomics for changes in common with PD that may describe risk of disease.

2020-07-16 | PXD018736 | Pride

Single-cell ATAC sequencing of SIINFEKL-reactive T cells in GL261 murine brain tumors in MHC class II deficient tumor-mircoenvironments

Project description:Single cell ATAC sequencing of SIINFEKL-reactive immune cell from intracranial murine GL261-SIINFEKL tumors 20 days after inoculation. SIINFEKL-reactive T cells were sorted based on dextramer staining. We show that loss of major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion.

2023-01-11 | E-MTAB-12512 | biostudies-arrayexpress

Multi-Omics and Informatics Analysis of FFPE Tissues Derived from Melanoma Patients with Long/Short Responses to Anti-PD1 Therapy Reveals Pathways of Response

Project description:Anti-PD-1 based immune therapies are thought to be dependent on antigen processing and presentation mechanisms. To characterize the immune-dependent mechanisms that predispose stage III/IV melanoma patients to respond to anti-PD-1 therapies, we performed a multi-omics study consisting of expression proteomics and targeted immune-oncology-based mRNA sequencing. Formalin-fixed paraffin-embedded tissue samples were obtained from stage III/IV patients with melanoma prior to anti-PD-1 therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed while on anti-PD-1 therapy for 1 year. We identified 263 protein/gene candidates that displayed differential expression, of which 223 were identified via proteomics and 40 via targeted-mRNA analyses. The downstream analyses of expression profiles using MetaCore software demonstrated an enrichment of immune system pathways involved in antigen processing/presentation and cytokine production/signaling. Pathway analyses showed interferon (IFN)-γ-mediated signaling via NF-κB and JAK/STAT pathways to affect immune processes in a cell-specific manner and to interact with the inducible nitric oxide synthase. We review these findings within the context of available literature on the efficacy of anti-PD-1 therapy. The comparison of good and poor responders, using efficacy of PD-1-based therapy at 1 year, elucidated the role of antigen presentation in mediating response or resistance to anti-PD-1 blockade.

2022-04-21 | PXD033340 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data