ORCID Profile
0000-0002-9682-1211
Current Organisation
Monash Biomedicine Discovery Institute, Monash University
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Publisher: Spandidos Publications
Date: 21-09-2016
Abstract: Baicalin, extracted and purified from the Chinese medicinal plant, Scutellaria baicalensis Georgi (Huang qin in Chinese), exhibits potent anti-inflammatory activity against asthma. However, it remains unknown whether baicalin inhibits the activity of CC chemokine receptor 7 (CCR7) and its ligands, which are crucial for the initiation of airway inflammation. In the present study, we investigated the effects of baicalin on CCR7 and its ligands, CCL19 and CCL21, as well as on the nuclear factor-κB (NF-κB) pathway in a mouse model of asthma. A mouse model of acute asthma was established by exposing the mice to ovalbumin (OVA) (by intraperitoneal injection and inhalational challenge). Within 24 h of the final OVA challenge, lung function was detected by direct airway resistance analysis. Lung tissues were examined for pathological changes. Inflammatory cell counts in bronchoalveolar lavage fluid (BALF) were assessed. ELISA was utilized to evaluate the OVA-IgE, CCL19 and CCL21 levels in BALF. The interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in serum were also detected by ELISA. The protein expression levels of CCR7, as well as that of phosphorylated IκBα (p-IκBα) and phosphorylated p65 (p-p65) were determined by western blot analysis and RT-qPCR was used to determine the CCR7 mRNA levels. Our data demonstrated that the oral administration of baicalin significantly improved pulmonary function and attenuated inflammatory cell infiltration into the lungs. Baicalin also decreased the levels of OVA-IgE, IL-6, TNF-α and CCR7, as well as those of its ligand, CCL19 the levels of NF-κB were also markedly suppressed by baicalin. The CCR7 mRNA level was substantially decreased. Our results thus suggest that baicalin exerts an inhibitory effect on airway inflammation, and this effect may be associated with the inhibition of CCR7 and CCL19/CCL21, which may provide new mechanistic insight into the anti‑inflammatory effects of baicalin.
Publisher: Oxford University Press (OUP)
Date: 2021
Abstract: Co-stimulation is a fundamental component of T cell biology and plays a key role in determining the quality of T cell proliferation, differentiation, and memory formation. T cell-based immunotherapies, such as chimeric antigen receptor (CAR) T cell immunotherapy, are no exception. Solid tumours have largely been refractory to CAR T cell therapy owing to an immunosuppressive microenvironment which limits CAR T cell persistence and effector function. In order to eradicate solid cancers, increasingly sophisticated strategies are being developed to deliver these vital co-stimulatory signals to CAR T cells, often specifically within the tumour microenvironment. These include designing novel co-stimulatory domains within the CAR or other synthetic receptors, arming CAR T cells with cytokines or using CAR T cells in combination with agonist antibodies. This review discusses the evolving role of co-stimulation in CAR T cell therapies and the strategies employed to target co-stimulatory pathways in CAR T cells, with a view to improve responses in solid tumours.
Publisher: American Association for Cancer Research (AACR)
Date: 02-09-2021
DOI: 10.1158/1078-0432.CCR-21-1141
Abstract: In this article, we describe a combination chimeric antigen receptor (CAR) T-cell therapy that eradicated the majority of tumors in two immunocompetent murine pancreatic cancer models and a human pancreatic cancer xenograft model. We used a dual-specific murine CAR T cell that expresses a CAR against the Her2 tumor antigen, and a T-cell receptor (TCR) specific for gp100. As gp100 is also known as pMEL, the dual-specific CAR T cells are thus denoted as CARaMEL cells. A vaccine containing live vaccinia virus coding a gp100 minigene (VV-gp100) was administered to the recipient mice to stimulate CARaMEL cells. The treatment also included the histone deacetylase inhibitor panobinostat (Pano). The combination treatment enabled significant suppression of Her2+ pancreatic cancers leading to the eradication of the majority of the tumors. Besides inducing cancer cell apoptosis, Pano enhanced CAR T-cell gene accessibility and promoted CAR T-cell differentiation into central memory cells. To test the translational potential of this approach, we established a method to transduce human T cells with an anti-Her2 CAR and a gp100-TCR. The exposure of the human T cells to Pano promoted a T-cell central memory phenotype and the combination treatment of human CARaMEL cells and Pano eradicated human pancreatic cancer xenografts in mice. We propose that patients with pancreatic cancer could be treated using a scheme that contains dual-specific CAR T cells, a vaccine that activates the dual-specific CAR T cells through their TCR, and the administration of Pano.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2022
DOI: 10.1158/2159-8290.CD-21-0694
Abstract: Tumors subvert antitumor immunity by engaging checkpoints that promote T-cell exhaustion. Here we identify PTP1B as an intracellular checkpoint and therapeutic target. We show that PTP1B is upregulated in intratumoral T cells and that its deletion or inhibition enhances T-cell antitumor activity and increases CAR T-cell effectiveness against solid tumors. This article is highlighted in the In This Issue feature, p. 587
Publisher: American Association for Cancer Research (AACR)
Date: 2022
DOI: 10.1158/2326-6074.TUMIMM21-PR04
Abstract: Chimeric Antigen Receptor T cell (CAR T) immunotherapy has been remarkably successful in the treatment of B-Cell Acute Lymphoblastic Leukemia (B-ALL). However, beyond hematological malignancies, CAR T cells have been ineffective in treating solid tumors. Novel approaches for enhancing the ability of CAR T cells to combat solid tumors are urgently required. Protein tyrosine phosphatases (PTPs) are enzymes that regulate a wide range of physiological processes including metabolism, cellular growth, proliferation and differentiation by controlling tyrosine phosphorylation-dependent signaling. PTPs are key regulators of T cell signaling and contribute to the maintenance of immune tolerance. Studies from our group have shown that PTPN2 plays pivotal role in negatively regulating T cell receptor (TCR) signaling by dephosphorylating and inactivating the Src family protein tyrosine kinase LCK (Wiede, Shields et al. 2011). PTPN2 also attenuates cytokine signaling by dephosphorylating JAK-1, JAK-3 and their target substrates STAT-1, -3 and -5 in a cell context-dependent manner (Simoncic, Lee-Loy et al. 2002, ten Hoeve, de Jesus Ibarra-Sanchez et al. 2002, Wiede, Shields et al. 2011, Wiede, La Gruta et al. 2014). Since CARs signal via LCK, and cytokine signaling is critical for CAR T cell function, we postulated that inhibiting PTPN2 might bolster the anti-tumor activity of CAR T cells. Here we used CRISPR-Cas9-ribonucleoprotein (RNP)-mediated genome editing to delete PTPN2 in CAR T cells. Using this approach PTPN2 was efficiently deleted in CAR T cells and the deletion of PTPN2 significantly enhanced the anti-tumor efficacy of CAR T cells in vitro and in vivo. This abstract is also being presented as Poster P004. Citation Format: Xin Du, Florian Wiede, Phillip K. Darcy, Tony Tiganis. CRISPR-mediated PTPN2 deletion in CAR T cells enhances anti-tumor efficacy [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy 2021 Oct 5-6. Philadelphia (PA): AACR Cancer Immunol Res 2022 (1 Suppl):Abstract nr PR04.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.ETAP.2016.07.005
Abstract: Ligustrazine which is isolated from Chinese herb ligusticum chuanxiong hort, has been widely used in traditional Chinese medicine (TCM) for asthma treatment. In this study, we aim to observe the effect of ligustrazine on inflammation and the associated chemokines and receptors in ovalbumin (OVA)-induced mouse asthma model. Our data demonstrates that ligustrazine suppresses airway hyperresponsiveness to methacholine and lung inflammation in OVA-induced mouse asthma model. Ligustrazine also induces inhibition of inflammatory cells including neutrophils, lymphocytes and eosinophils. In addition, ligustrazine significantly reduces IL-4, IL-5, IL-17A, CCL3, CCL19 and CCL21 level in BALF of asthma mice. Furthermore, ligustrazine induces down-regulation of CCL19 receptor CCR7, STAT3 and p38 MAPK protein expression. Collectively, these results suggest that ligustrazine is effective in attenuation of allergic airway inflammatory changes and related chemokines and receptors in OVA-induced asthma model, and this action might be associated with inhibition of STAT3 and p38 MAPK pathway, which indicates that ligustrazine may be used as a potential therapeutic method to treat asthma.
Publisher: EMBO
Date: 28-04-2022
Publisher: Public Library of Science (PLoS)
Date: 06-02-2015
Location: Australia
No related grants have been discovered for Xin Du.