ORCID Profile
0000-0001-9607-0000
Current Organisations
The Harry Perkins Institute of Medical Research
,
University of Western Australia
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Publisher: Wiley
Date: 20-04-2018
DOI: 10.1002/PATH.5080
Publisher: Oxford University Press (OUP)
Date: 28-05-2003
Publisher: Informa UK Limited
Date: 11-2012
DOI: 10.4161/ONCI.20981
Publisher: Elsevier BV
Date: 08-2010
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2017
DOI: 10.1158/0008-5472.CAN-16-3129
Abstract: T-cell infiltration of solid tumors is associated with improved prognosis and favorable responses to immunotherapy. Mechanisms that enable tumor infiltration of CD8+ T cells have not been defined, nor have drugs that assist this process been discovered. Here we address these issues with a focus on VE-cadherin, a major endothelial cell–specific junctional protein that controls vascular integrity. A decrease in VE-cadherin expression is associated with tumor pathology. We developed an oligonucleotide-based inhibitor (CD5-2), which disrupted the interaction of VE-cadherin with its regulator miR-27a, resulting in increased VE-cadherin expression. Administration of CD5-2 in tumor-bearing mice enhanced expression of VE-cadherin in tumor endothelium, activating TIE-2 and tight junction pathways and normalizing vessel structure and function. CD5-2 administration also enhanced tumor-specific T-cell infiltration and spatially redistributed CD8+ T cells within the tumor parenchyma. Finally, CD5-2 treatment enhanced the efficacy of anti-PD-1 blocking antibody. Our work establishes a role for VE-cadherin in T-cell infiltration in tumors and offers a preclinical proof of concept for CD5-2 as a therapeutic modifier of cancer immunotherapy via effects on the tumor vasculature. Cancer Res 77(16) 4434–47. ©2017 AACR.
Publisher: Elsevier BV
Date: 2014
DOI: 10.1016/J.MOLMED.2013.10.002
Abstract: Stroma is an integral part of solid tumors and plays a key role in growth promotion and immune suppression. Most current therapies focus on destroying tumors and/or abnormal vasculature. However, evidence is emerging that anticancer efficacy improves with vessel normalization rather than destruction. Specific targeting of cytokines into tumors provides proof-of-concept that tumor stroma is dynamic and can be remodeled to increase drug access and alleviate immune suppression. Changing the inflammatory milieu 'opens' tumors for therapy and thus provides a license for destruction. This involves reprogramming of paracrine signaling networks between multiple stromal components to break the vicious cycle of angiogenesis and immune suppression. With active immunotherapy rapidly moving into the clinic, local cytokine delivery emerges as an attractive adjuvant.
Publisher: Wiley
Date: 17-09-2004
DOI: 10.1002/PROS.20163
Abstract: In several malignant tissues, the angiopoietins are principal regulators of vascular growth and regression, but in normal prostate and prostate tumors the role of the angiopoietins is unknown. Angiopoietin (ang) 1 and 2 were immunolocalized in TUR-diagnosed prostate tumors with long follow-up and the expression was related to vascular density and clinicopathological variables. Ang 1 was strongly expressed in the basal epithelial cell layer in non-malignant tissue, whereas tumors had lower levels localized to the epithelial cells. A weak ang 2 immunoreaction was observed in non-malignant tissue and in low to intermediate Gleason score (GS) tumors, with a similar expression pattern. However, most high GS tumors showed an intense ang 2 staining. Ang 2 was significantly correlated to GS, density of endoglin stained blood vessels, metastases, and to cancer specific survival. We conclude that ang 2 probably is an important regulator of angiogenesis in prostate cancer.
Publisher: Frontiers Media SA
Date: 27-05-2021
DOI: 10.3389/FIMMU.2021.674375
Abstract: Improving the effectiveness of anti-cancer immunotherapy remains a major clinical challenge. Cytotoxic T cell infiltration is crucial for immune-mediated tumor rejection, however, the suppressive tumor microenvironment impedes their recruitment, activation, maturation and function. Nevertheless, solid tumors can harbor specialized lymph node vasculature and immune cell clusters that are organized into tertiary lymphoid structures (TLS). These TLS support naïve T cell infiltration and intratumoral priming. In many human cancers, their presence is a positive prognostic factor, and importantly, predictive for responsiveness to immune checkpoint blockade. Thus, therapeutic induction of TLS is an attractive concept to boost anti-cancer immunotherapy. However, our understanding of how cancer-associated TLS could be initiated is rudimentary. Exciting new reagents which induce TLS in preclinical cancer models provide mechanistic insights into the exquisite stromal orchestration of TLS formation, a process often associated with a more functional or “normalized” tumor vasculature and fueled by LIGHT/LTα/LTβ, TNFα and CC/CXC chemokine signaling. These emerging insights provide innovative opportunities to induce and shape TLS in the tumor microenvironment to improve immunotherapies.
Publisher: MDPI AG
Date: 27-03-2012
Publisher: Springer Science and Business Media LLC
Date: 11-09-2017
DOI: 10.1038/NI.3836
Abstract: The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.
Publisher: The Endocrine Society
Date: 08-2005
DOI: 10.1210/EN.2004-1480
Abstract: The involution of the rat ventral prostate gland after castration could be caused by primary changes in the vasculature. To explore the mechanisms, we studied the effects of castration and testosterone treatment on the vasculature in the ventral prostate in adult rats and mice. Androgen receptor expression, vascular morphology, and the expression of angiopoietin (ang) 1 and 2 and their receptor tie 2 were examined 1, 3, and 7 d after castration and after testosterone treatment of castrated animals using stereological methods, immunohistochemistry, laser capture microdissection, and Western blotting. One day after castration, the percentage of blood vessels covered with smooth muscle actin, endothelial cell proliferation, and vascular volume had decreased, whereas endothelial cell apoptosis had increased. Simultaneously, ang 1 and tie 2 protein levels decreased. Nuclear expression of androgen receptor was observed not only in glandular and stroma smooth muscle cells but also in the mural cells of prostate arteries and veins and was markedly down-regulated already 1 d after castration. Testosterone administration of castrated mice and rats reversed all the observed effects. At the mRNA level, tie 2 was exclusively, but ang 1 predominantly, expressed in the stroma, compared with the epithelial compartment. Local delivery of soluble tie 2 during testosterone-stimulated growth, inhibited vascular maturation and increased vascular volume and leukocyte infiltration compared with controls. We conclude that androgens may regulate the prostate vasculature by direct effects on mural vascular cells and by influencing the secretion of the angiopoietins, in above all, the stroma cells.
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.CELREP.2019.12.013
Abstract: Due to limited current therapies, metastases are the primary cause of mortality in cancer patients. Here, we employ a fusion compound of the cytokine LIGHT and a vascular targeting peptide (LIGHT-VTP) that homes to angiogenic blood vessels in primary tumors. We show in primary mouse lung cancer that normalization of tumor vasculature by LIGHT-VTP prevents cancer cell intravasation. Further, LIGHT-VTP efficiently targets pathological blood vessels in the pre-metastatic niche, reducing vascular hyper-permeability and extracellular matrix (ECM) deposition, thus blocking metastatic lung colonization. Moreover, we demonstrate that mouse and human metastatic melanoma deposits are targetable by VTP. In overt melanoma metastases, LIGHT-VTP normalizes intra-metastatic blood vessels and increases GrzB
Publisher: Wiley
Date: 13-09-2007
DOI: 10.1002/PROS.20657
Abstract: Castration results in a major involution of the normal prostate gland. This process is initiated by effects in the prostate stroma and vasculature. Castration-induced regression of androgen sensitive prostate tumors is however less prominent and hypothetically this could be related to a limited stromal/vascular response. We therefore used animal tumor models to explore the importance of stroma and vascular effects, and if castration effects could be enhanced by a simultaneous therapy targeting the tumor stroma. Using rats with Dunning PAP and H tumors, stereological methods, immunohistochemistry, and Western blotting, we studied the tumor response 7 and 28 days after castration and after the addition of stroma targeted therapies. In the normal ventral prostate (VP) nuclear androgen receptors (AR) were rapidly downregulated after castration. In contrast, the Dunning tumors downregulated the AR in the cancerous epithelium, but not in the surrounding stroma. Vascular regulators such as the angiopoietins, tie 2, and PDGF-Rbeta were not decreased in the stroma after castration, as observed in the VP, creating an environment that prevents vascular involution. When a tumor stroma targeted therapy inhibiting the tie 2 receptor and the PDGF-Rbeta simultaneously was added to castration it resulted in a decreased vascular density, increased tumor cell apoptosis and decreased tumor growth compared to castration alone. The stroma in highly differentiated androgen sensitive Dunning tumors is apparently androgen insensitive. If this unresponsive stroma is targeted the effects of castration can be enhanced.
Publisher: MDPI AG
Date: 10-05-2021
Abstract: Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients , visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III–IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.BBCAN.2015.06.001
Abstract: Current clinical success with anti-cancer immunotherapy provides exciting new treatment opportunities. While encouraging, more needs to be done to induce durable effects in a higher proportion of patients. Increasing anti-tumor effector T cell quantity or quality alone does not necessarily correlate with therapeutic outcome. Instead, the tumor microenvironment is a critical determinant of anti-cancer responsiveness to immunotherapy and can confer profound resistance. Yet, the tumor-promoting environment - due to its enormous plasticity - also delivers the best opportunities for adjuvant therapy aiming at recruiting, priming and sustaining anti-tumor cytotoxicity. While the tumor environment as an entity is increasingly well understood, current interventions are still broad and often systemic. In contrast, tumors grow in a highly compartmentalized environment which includes the vascular erivascular niche, extracellular matrix components and in some tumors lymph node aggregates all of these structures harbor and instruct subsets of immune cells. Targeting and re-programming specific compartments may provide better opportunities for adjuvant immunotherapy.
Publisher: Wiley
Date: 22-09-2010
Publisher: Proceedings of the National Academy of Sciences
Date: 30-04-2012
Abstract: Solid tumors are intrinsically resistant to immune rejection. Abnormal tumor vasculature can act as a barrier for immune cell migration into tumors. We tested whether targeting IFNγ and/or TNFα into pancreatic neuroendocrine tumors can alleviate immune suppression. We found that intratumoral IFNγ causes rapid vessel loss, which does not support anti-tumor immunity. In contrast, low-dose TNFα enhances T-cell infiltration and overall survival, an effect that is exclusively mediated by CD8 + effector cells. Intriguingly, lymphocyte influx does not correlate with increased vessel leakiness. Instead, low-dose TNFα stabilizes the vascular network and improves vessel perfusion. Inflammatory vessel remodeling is, at least in part, mediated by tumor-resident macrophages that are reprogrammed to secrete immune and angiogenic modulators. Moreover, inflammatory vessel remodeling with low-dose TNFα substantially improves antitumor vaccination or adoptive T-cell therapy. Thus, low-dose TNFα promotes both vessel remodeling and antitumor immune responses and acts as a potent adjuvant for active immunotherapy.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.CELREP.2015.12.004
Abstract: Normalization of the tumor vasculature is an emerging concept shown to improve anti-cancer therapy. However, there are currently no clinical interventions that effect long-lasting normalization. Here, we have developed a strategy for normalization by specific intratumoral delivery of LIGHT/TNFSF14. Importantly, normalization occurs by induced expression of contractile markers in intratumoral pericytes, which in turn re-establishes tight pericyte-vessel alignment. Restoring vessel integrity improves tumor perfusion and acts as adjuvant to chemo- and immunotherapy. Mechanistically, intratumoral LIGHT induces pericyte differentiation and normalization via Rho kinase signaling. Minute amounts of LIGHT act in a paracrine fashion to trigger an lifying cascade involving transforming growth factor β (TGF-β) from peri-vascular macrophages. That these effects can be reproduced by adoptive transfer of LIGHT-stimulated macrophages alone demonstrates their central role in regulating pericyte differentiation. Our findings highlight a crucial role of pericyte contractile properties in vascular normalization, effected by macrophage signaling, thus providing so far unexplored anti-cancer opportunities.
Publisher: Elsevier BV
Date: 10-2018
Abstract: The density of intratumoral CD8
No related grants have been discovered for Anna Johansson.