Biology subjects

Nee, E.

Publications and source records attributed to Nee, E..

3 recordsLinked to original sources

bioRxiv2024

Ex vivo Model of Functioning Human Lymph Node Reveals Pivotal Role for Innate Lymphoid Cells and Stromal Populations in Response to Vaccine Adjuvant

Immunological processes that underpin the administration of therapeutics and vaccines are poorly defined due to a lack of models which faithfully recapitulate human immune responses. Inbred mice lack the diversity inherent to people, while the microanatomical organisation of human tissue is lost in isolated cell suspensions. We describe precision-cut human lymph node (LN) slices as architecturally-preserved, functioning lymphoid tissue model system, and explore early inflammatory responses to a potent vaccine liposomal adjuvant containing a TLR4-agonist and QS21 saponin. Combining scRNA-seq, multiplexed immunofluorescence and secretome analysis, we dissect direct and indirect signalling pathways in both leukocytes and stromal cells to reveal communication networks linking innate and adaptive immunity. Application of molecular inhibitors reveals that secretion of IL-1{beta}, but not IL-18, is TLR4-dependent in human LN. Retaining donor-to-donor immune variation, this ex vivo LN model system enables the study of pathways previously difficult to observe in humans, paving the way towards precision medicine.

immunology↗

bioRxiv2024

Chemoresistance of TP53 mutant AML requires the mevalonate byproduct, GGPP, for regulation of ROS and induction of a mitochondria stress response

Acute myeloid leukemia (AML) with mutations in the tumor suppressor gene, TP53 (TP53mut AML), is fatal with a median survival of only 6 months. RNA sequencing on purified AML patient samples show TP53mut AML has higher expression of mevalonate pathway genes. We retrospectively identified a survival benefit in TP53mut AML patients who received chemotherapy concurrently with a statin, which inhibits the mevalonate pathway. Mechanistically, TP53mut AML resistance to standard AML chemotherapy, cytarabine (AraC), correlates with increased mevalonate pathway activity and a mitochondria stress response with increased mitochondria mass and oxidative phosphorylation. Pretreatment with a statin reverses these effects and chemosensitizes TP53mut AML cell lines and primary samples in vitro and in vivo. Mitochondria-dependent chemoresistance requires the geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway and novel GGPP-dependent synthesis of glutathione to manage AraC-induced reactive oxygen species (ROS). Overall, we show that the mevalonate pathway is a novel therapeutic target in TP53mut AML. SignificanceChemotherapy-persisting TP53mut AML cells induce a mitochondria stress response that requires mevalonate byproduct, GGPP, through its novel role in glutathione synthesis and regulation of mitochondria metabolism. We provide insight into prior failures of the statin family of mevalonate pathway inhibitors in AML. We identify clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of TP53mut AML.

cancer biology↗

bioRxiv2023

A longitudinal single-cell therapeutic atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease

Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires an understanding of how cellular networks change following therapy. We describe a therapeutic atlas for Crohns disease (CD) and ulcerative colitis (UC) following anti-tumour necrosis factor (TNF) therapy. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies from 38 patients and three controls, revealing disease- and therapy-specific differences. A systems-biology analysis identified distinct spatially-resolved cellular microenvironments: granuloma signatures in CD and interferon (IFN)-response signatures localising to T-cell aggregates and epithelial damage in CD and UC. Longitudinal comparisons demonstrated that disease progression in non-responders associated with myeloid and stromal cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas informs drug positioning across IMIDs, and suggests a rationale for the use of janus kinase (JAK) inhibition following anti-TNF resistance.

immunology↗