A5058971471- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- PI3K/AKT/mTOR signaling in cancer
- Chronic Lymphocytic Leukemia Research
- Lymphoma Diagnosis and Treatment
- Immune Response and Inflammation
- Immune cells in cancer
- Cell Image Analysis Techniques
- Cancer Research and Treatments
- Cancer Genomics and Diagnostics
- Single-cell and spatial transcriptomics
- Histone Deacetylase Inhibitors Research
- Monoclonal and Polyclonal Antibodies Research
- Cytokine Signaling Pathways and Interactions
- RNA modifications and cancer
- Sarcoma Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Cell Adhesion Molecules Research
- Asthma and respiratory diseases
- Inflammatory mediators and NSAID effects
- interferon and immune responses
Flagship Pioneering (United States)
2023-2024
Bristol-Myers Squibb (United States)
2021-2023
AstraZeneca (United Kingdom)
2018-2022
AstraZeneca (Canada)
2018
Emory University
2015-2017
Medical Research Council
2010-2014
Emory Healthcare
2014
The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary epithelial cells (mTECs) provide spectrum tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge developing repertoire specificities. Despite this role, mechanisms Aire(+) mTEC development remain unclear, particularly those stages that occur post-Aire expression represent terminal...
Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that mechanistic target rapamycin (mTOR)-dependent metabolic adaptation was required at discrete locations. mTOR dispensable for dendritic cell (DC) in secondary lymphoid tissues necessary to regulate cellular metabolism and accumulation CD103+ DCs alveolar macrophages lung. Moreover, while numbers...
Background The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate activity and augment immunity providing therapeutic benefit...
To investigate the temporal regulation of commitment immature thymocytes to either CD4(+) or CD8(+) lineage in thymus, we developed a transgenic mouse that expressed tetracycline-inducible gene encoding tyrosine kinase zeta chain-associated protein 70 kD (Zap70), which restored development Zap70(-/-) arrested at preselection, CD4(+)CD8(+) double-positive (DP) stage. After induction expression Zap70 and production protein, single-positive (SP) cells Zbtb7b (which encodes T cell-associated...
It has long been recognized that the T-cell compartment more CD4 helper than CD8 cytotoxic T cells, and this is most evident looking at development in thymus. However, it remains unknown how thymocyte so favors lineage development. To identify basis of asymmetry, we analyzed synchronized cohorts thymocytes vivo estimated rates death differentiation throughout development, inferring lineage-specific efficiencies selection. Our analysis suggested roughly equal numbers cells each enter...
PI3K inhibitors with differential selectivity to distinct isoforms have been tested extensively in clinical trials, largely target tumor epithelial cells. signaling also regulates the immune system and inhibition of PI3Kδ modulate microenvironment pre-clinical mouse models by relieving T-regs-mediated immunosuppression. as a class specifically are associated immune-related side effects. However, impact mixed immunology is under-explored. Here we examine effects AZD8835, dual PI3Kα/δ...
The developmental pathways of regulatory T cells (T(reg)) generation in the thymus are not fully understood. In this study, we reconstituted thymic development Zap70-deficient thymocytes with a tetracycline-inducible Zap70 transgene to allow temporal dissection T(reg) development. We find that develop distinctive kinetics, first appearing by day 4 among CD4 single-positive (SP) thymocytes. Accepted models CD25(+)Foxp3(+) selection suggest via CD25(+)Foxp3(-) SP precursors. contrast, our...
mTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent net benefit be contraindicated the of immunooncology therapies is less understood. Here, we report that mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity combination with anti-CTLA-4 (αCTLA-4), αPD-1 αPD-L1 checkpoint blockade. Combination and blocking antibodies led to tumour growth improved survival MC-38 CT-26 pre-clinical syngeneic...
Flow cytometry is a mainstay technique in cell biology research, where it used for phenotypic analysis of mixed populations. Quantitative approaches have unlocked deeper value flow drug discovery research. As the number modalities and druggable mechanisms increases, there an increasing drive to identify meaningful biomarkers, evaluate relationship between pharmacokinetics pharmacodynamics (PK/PD), translate these insights into evaluation patients enrolled early clinical trials. In this...
T cell receptor signaling in thymocytes determines their responsiveness to a survival cytokine later life.
Abstract TCR signaling plays a central role in directing developmental fates of thymocytes. Current models suggest signal duration directs CD4 versus CD8 lineage development. To investigate the during positive selection directly, we switched off cohort selecting thymocytes and followed, time, their subsequent fate. We did this using an inducible Zap70 transgenic mouse model that allowed Zap70-dependent to be turned on then again. Surprisingly, loss CD4+CD8lo not prevent development into...
Abstract Regulatory T cells (Treg) critically maintain immuno-suppression in the tumor microenvironment, representing an attractive immuno-oncology target. The Treg lineage is defined by expression of FOXP3 transcription factor, which controls immune-suppressive functions. We have developed clinical candidate AZD8701, a next-generation antisense oligonucleotide inhibitor (utilizing Ionis Gen 2.5 cEt-modified ASO platform). AZD8701 treatment knocked down primary human Tregs via free uptake...
During positive selection of CD4 + , CD8 double (DP) thymocytes, expression the tyrosine kinase Zap70 is subject to developmental regulation. Signalling downstream T‐cell receptor (TCR) induces expression, forming a feedback circuit. Although previous studies show this circuit required for generation lineage cells, it not known whether T cells also depends on intact regulation Zap70. To address this, we analysed development Class II‐restricted thymocytes in mice lacking transcriptional...
Article5 May 2022Open Access Transparent process A preclinical model of peripheral T-cell lymphoma GATA3 reveals DNA damage response pathway vulnerability Elizabeth Kuczynski Corresponding Author [email protected] orcid.org/0000-0002-6924-6848 Oncology R&D, AstraZeneca, Cambridge, UK Contribution: Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, review & editing Search for more papers by this author Giulia...
T cell hematological cancer has a complex interplay with host immune cells, but the ability to experimentally discriminate transferred cells from by flow cytometry is technically challenging. Here, we present protocol evaluate and phenotypes following transplant of lymphoma bearing congenic marker (CD45.2) into syngeneic (CD45.1). We describe steps for isolation primary mice, staining preparation antibody cocktails, analysis cytometry. For complete details on use execution this protocol,...
Abstract Regulatory T-cells (Treg) contribute to cancer progression by suppressing anti-tumor immuity. Tregs specifically require expression of the lineage defining transcription factor Foxp3 for their development and function, but this protein cannot be targeted with conventional small molecule or biologic drugs. We employed next-generation antisense inhibitors (Gen 2.5 cEt-modified ASOs) in an attempt selectively inhibit mouse Treg cells, evaluated consequences ASO-mediated knock-down...
Immune-checkpoint blockade (ICB) has transformed the landscape of cancer treatment. However, there is much to understand around refractory or acquired resistance in patients order utilize ICB therapy its full potential. In this perspective article, we discuss opportunities and challenges that are emerging as our understanding immuno-oncology matures. Firstly, been remarkable progress made exquisite overlap between oncogenic immune signaling pathways. Several cancer-signaling pathways...
Abstract Foxp3 + Regulatory T cells (Treg) are a subset of CD4 that play critical functions in maintaining tolerance to self antigens and suppressing autoimmunity, regulating immune responses pathogens have role the pathophysiology anti-tumoural immunity. Treg ontogeny is complex since they generated following recognition thymus during normal cell development (thymic Treg), but also induced from mature conventional when activated by foreign antigen with appropriate additional cues (inducible...
Abstract Intricate overlap between environmental and pathogen derived signals regulate innate immunity, the mechanistic target of rapamycin (mTOR) kinase is a key signal integrator. Recent reports show mTOR inhibition increases proinflammatory activity DCs in vitro, suggesting that DC-targeted inhibitors could adjuvant immunity. We deleted using CD11c Cre/LoxP system (mTOR DCKO), challenged mice with distinct immunological stimuli. In contrast to our expectations, we found no inflammatory...
<h3>Background</h3> The aryl hydrocarbon receptor (AHR) is a transcription factor activated by several endogenous and exogenous ligands which regulate the activity of immune cells. Endogenous AHR ligand concentrations are elevated in tumor microenvironment (TME). Cells expressing IDO1, TDO2, IL4I1, produce kynurenine kynurenic acid, leading to pathway activation suppression anti-tumor immunity. Efforts target production using IDO1 TDO2 inhibitors have failed clinic. We hypothesize that...
Abstract Regulatory T cells (Treg) contribute to the progression of cancer through suppression specific anti-tumor effector immune responses. Therefore, inhibition Treg function is an attractive approach for immunotherapy. However, despite substantial effort, Tregs remains a challenge. Foxp3 Treg-specific transcription factor required their development and function. We employed next-generation antisense inhibitors (Gen 2.5 cEt-modified ASOs) selectively inhibit expression in mouse evaluated...