ORCID Profile
0000-0001-6060-0065
Current Organisations
Walter and Eliza Hall Institute of Medical Research
,
The University of Auckland
,
Auckland Uniservices Limited
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Publisher: MDPI AG
Date: 23-08-2021
Abstract: In recent decades, adoptive cell transfer and checkpoint blockade therapies have revolutionized immunotherapeutic approaches to cancer treatment. Advances in whole exome/genome sequencing and bioinformatic detection of tumour-specific genetic variations and the amino acid sequence alterations they induce have revealed that T cell mediated anti-tumour immunity is substantially directed at mutated peptide sequences, and the identification and therapeutic targeting of patient-specific mutated peptide antigens now represents an exciting and rapidly progressing frontier of personalized medicine in the treatment of cancer. This review outlines the historical identification and validation of mutated peptide neoantigens as a target of the immune system, and the technical development of bioinformatic and experimental strategies for detecting, confirming and prioritizing both patient-specific or “private” and frequently occurring, shared “public” neoantigenic targets. Further, we examine the range of therapeutic modalities that have demonstrated preclinical and clinical anti-tumour efficacy through specifically targeting neoantigens, including adoptive T cell transfer, checkpoint blockade and neoantigen vaccination.
Publisher: Wiley
Date: 02-08-2016
DOI: 10.1038/ICB.2016.56
Abstract: The homeostatic chemokine CCL21 has a pivotal role in lymphocyte homing and compartment localisation within the lymph node, and also affects adhesion between immune cells. The effects of CCL21 are modulated by its mode of presentation, with different cellular responses seen for surface-bound and soluble forms. Here we show that plasmin cleaves surface-bound CCL21 to release the C-terminal peptide responsible for CCL21 binding to glycosaminoglycans on the extracellular matrix and cell surfaces, thereby generating the soluble form. Loss of this anchoring peptide enabled the chemotactic activity of CCL21 and reduced cell tethering. Tissue plasminogen activator did not cleave CCL21 directly but enhanced CCL21 processing through generation of plasmin from plasminogen. The tissue plasminogen activator inhibitor neuroserpin prevented processing of CCL21 and blocked the effects of soluble CCL21 on cell migration. Similarly, the plasmin-specific inhibitor α
Publisher: MDPI AG
Date: 31-08-2020
DOI: 10.20944/PREPRINTS202008.0728.V1
Abstract: T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically & lsquo exhausted& rsquo in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.
Publisher: Public Library of Science (PLoS)
Date: 30-04-2013
Publisher: American Chemical Society (ACS)
Date: 16-08-2019
DOI: 10.1021/ACS.JMEDCHEM.9B01044
Abstract: Cancer immunotherapy has gained increasing attention due to its potential specificity and lack of adverse side effects when compared to more traditional modes of treatment. Toll-like receptor 2 (TLR2) agonists are lipopeptides possessing the
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1283
Publisher: Springer Science and Business Media LLC
Date: 12-2011
Abstract: Nonstructural glycoprotein 4 (NSP4) encoded by rotavirus is the only viral protein currently believed to function as an enterotoxin. NSP4 is synthesized as an intracellular transmembrane glycoprotein and as such is essential for virus assembly. Infection of polarized Caco-2 cells with rotavirus also results in the secretion of glycosylated NSP4 apparently in a soluble form despite retention of its transmembrane domain. We have examined the structure, solubility and cell-binding properties of this secreted form of NSP4 to further understand the biochemical basis for its enterotoxic function. We show here that NSP4 is secreted as discrete detergent-sensitive oligomers in a complex with phospholipids and demonstrate that this secreted form of NSP4 can bind to glycosaminoglycans present on the surface of a range of different cell types. NSP4 was purified from the medium of infected cells after ultracentrifugation and ultrafiltration by successive lectin-affinity and ion exchange chromatography. Oligomerisation of NSP4 was examined by density gradient centrifugation and chemical crosslinking and the lipid content was assessed by analytical thin layer chromatography and flame ionization detection. Binding of NSP4 to various cell lines was measured using a flow cytometric-based assay. Secreted NSP4 formed oligomers that contained phospholipid but dissociated to a dimeric species in the presence of non-ionic detergent. The purified glycoprotein binds to the surface of various non-infected cells of distinct lineage. Binding of NSP4 to HT-29, a cell line of intestinal origin, is saturable and independent of alent cations. Complementary biochemical approaches reveal that NSP4 binds to sulfated glycosaminoglycans on the plasma membrane. Our study is the first to analyze an authentic (i.e. non-recombinant) form of NSP4 that is secreted from virus-infected cells. Despite retention of the transmembrane domain, secreted NSP4 remains soluble in an aqueous environment as an oligomeric lipoprotein that can bind to various cell types via an interaction with glycosaminoglycans. This broad cellular tropism exhibited by NSP4 may have implications for the pathophysiology of rotavirus disease.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JHEP.2019.06.028
Abstract: To evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV. In a phase Ib study, patients received either a single dose of nivolumab at 0.1 mg/kg (n = 2) or 0.3 mg/kg (n = 12), or 40 yeast units of GS-4774 at baseline and week 4 and 0.3 mg/kg of nivolumab at week 4 (n = 10). The primary efficacy endpoint was mean change in HBV surface antigen (HBsAg) 12 weeks after nivolumab. Safety and immunologic changes were assessed through week 24. There were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T cell PD-1 receptor occupancy 6-12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75-77), and no significant differences were observed between cohorts (p = 0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of -0.30 (95% CI -0.46 to -0.14) and -0.16 (95% CI -0.33 to 0.01) log In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in 1 patient. Chronic hepatitis B virus infection (CHB) is characterized by a dysfunctional immune response. In patients with CHB, inhibitory receptors, such as programmed death receptor 1 (PD-1) are overexpressed on T cells, leading to an ineffective immune response in the liver. Herein, we show that the PD-1 inhibitor, nivolumab, is safe and effective for the treatment of virally suppressed patients with CHB. Australian New Zealand Clinical Trials Registry (www.anzctr.org.au/) number: ACTRN12615001133527.
Publisher: Oxford University Press (OUP)
Date: 10-02-2015
Abstract: Contact between T cells and APCs and activation of an effective immune response trigger cellular polarization and the formation of a structured interface known as the immunological synapse. Interactions across the synapse and secretion of T cell and APC-derived factors into the perisynaptic compartment regulate synapse formation and activation of T cells. We report that the serine protease inhibitor neuroserpin, an axonally secreted protein thought to play roles in the formation of the neuronal synapse and refinement of synaptic activity, is expressed in human nai¨ve effector memory and central memory subsets of CD4+ and CD8+ T cells, as well as monocytes, B cells, and NK cells. Neuroserpin partially colocalized with a TGN38/LFA-1-positive vesicle population in T cells and translocates to the immunological synapse upon activation with TCR antibodies or antigen-pulsed APCs. Activation of T cells triggered neuroserpin secretion, a rapid, 8.4-fold up-regulation of the serine protease tissue plasminogen activator, the protease target for neuroserpin, and a delayed, 6.25-fold down-regulation of neuroserpin expression. Evidence of polarization and regulated neuroserpin expression was also seen in ex vivo analyses of human lymph nodes and blood-derived T cells. Increased neuroserpin expression was seen in clusters of T cells in the paracortex of human lymph nodes, with some showing polarization to areas of cell:cell interaction. Our results support a role for neuroserpin and tissue plasminogen activator in activation-controlled proteolytic cleavage of proteins in the synaptic or perisynaptic space to modulate immune cell function.
Publisher: Springer Science and Business Media LLC
Date: 21-10-2014
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5OB00822K
Abstract: The facile preparation of cell-targeted platinum nanoparticles (PtNPs) is described, using designed peptides that as a single molecule control PtNP cluster growth, stabilise clusters in aqueous suspension and enable attachment of a versatile range of cell-targeting ligands.
Publisher: MDPI AG
Date: 05-10-2020
DOI: 10.3390/IJMS21197357
Abstract: T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically “exhausted” in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.
Location: Australia
No related grants have been discovered for Daniel Verdon.