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Publications
Publications (192)
Mesothelioma is characterised by its aggressive invasive behaviour, affecting the surrounding tissues of the pleura or peritoneum. We compared an invasive pleural model with a non-invasive subcutaneous model of mesothelioma and performed transcriptomic analyses on the tumour samples. Invasive pleural tumours were characterised by a transcriptomic s...
While chemotherapy remains the first-line treatment for many cancers, it is still unclear what distinguishes responders from non-responders. Here, we characterize the chemotherapy-responsive tumor microenvironment in mice, using RNA sequencing on tumors before and after cyclophosphamide, and compare the gene expression profiles of responders with p...
Mesothelioma is characterised by its aggressive invasive behaviour, affecting the surrounding tissues of the pleura or peritoneum. We compared an invasive pleural model with a non-invasive subcutaneous model of mesothelioma and performed transcriptomic analyses on the tumour samples. Invasive pleural tumours were characterised by a transcriptomic s...
The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tum...
Chemotherapy has historically been the mainstay of cancer treatment, but our understanding of what drives a successful therapeutic response remains limited. The diverse response of cancer patients to chemotherapy has been attributed principally to differences in the proliferation rate of the tumor cells, but there is actually very little experiment...
Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA‐4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune ch...
Immune checkpoint therapy (ICT) causes durable tumor responses in a subgroup of patients. Profiling T cell receptor beta (TCRβ) repertoire structure in ICT responders and non-responders provides mechanistic insight into what constitutes an effective anti-tumor response, and could result in the development of predictive biomarkers of response to ide...
With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin pre...
Mesothelioma is a cancer that typically originates in the pleura of the lungs. It rapidly invades the surrounding tissues, causing pain and shortness of breath. We compared cell lines injected either subcutaneously or intrapleurally and found that only the latter resulted in invasive and rapid growth. Pleural tumours displayed a transcriptional sig...
A correction to this paper has been published: https://doi.org/10.1007/s00262-021-02970-z
Little is known about the dynamic biological events that underpin therapeutic efficacy in immune checkpoint blockade (ICB) in cancer, due to the inability to frequently sample tumors in patients. Here, we mapped the transcriptional profiles of 144 responding and non-responding tumors within two mouse models at four time points during ICB. We found...
Thoracic cancers pose a significant global health burden. Immune checkpoint blockade therapies have improved treatment outcomes, but durable responses remain limited. Understanding how the host immune system interacts with a developing tumor is essential for the rational development of improved treatments for thoracic malignancies. Recent technical...
The success of immunotherapy that targets inhibitory T cell receptors for the treatment of multiple cancers has seen the anti-tumor immune response re-emerge as a promising biomarker of response to therapy. Longitudinal characterization of T cells in the tumor microenvironment (TME) helps us understand how to promote effective anti-tumor immunity....
Background: Single-agent cyclophosphamide can deplete regulatory T-cells (Treg). We aimed to determine optimal dosing and scheduling of oral cyclophosphamide, alongside pemetrexed-based chemotherapy, to deplete Treg in mesothelioma or non-small-cell lung cancer patients.
Methods: 31 Patients received pemetrexed +/- cisplatin or carboplatin on day 1...
Immune checkpoint therapy (ICT) results in durable responses in individuals with some cancers, but not all patients respond to treatment. ICT improves CD8+ cytotoxic T lymphocyte (CTL) function, but changes in tumor antigen-specific CTLs post-ICT that correlate with successful responses have not been well characterized. Here, we studied murine tumo...
Immunotherapies have revolutionized cancer treatment. In particular, immune checkpoint therapy (ICT) leads to durable responses in some patients with some cancers. However, the majority of treated patients do not respond. Understanding immune mechanisms that underlie responsiveness to ICT will help identify predictive biomarkers of response and dev...
Objective:
There is substantial evidence that exercise can safely reduce the risk of cancer and improve survival in different human cancer populations. Long latency periods associated with carcinogen-induced cancers like asbestos induced mesothelioma provide an opportunity to implement exercise as an intervention to delay or prevent disease develo...
Objective
There is substantial evidence that exercise can safely reduce the risk of cancer and improve survival in different human cancer populations. Long latency periods associated with carcinogeninduced cancers like asbestos induced mesothelioma provide an opportunity to implement exercise as an intervention to delay or prevent disease developme...
Objective: There is substantial evidence that exercise can safely reduce the risk of cancer and improve survival in different human cancer populations. Long latency periods associated with carcinogen‑induced cancers like asbestos induced mesothelioma provide an opportunity to implement exercise as an intervention to delay or prevent disease develop...
The therapeutic response to immune checkpoint blockade (ICB) is highly variable, not only between different cancers but also between patients with the same cancer type. The biological mechanisms underlying these differences in response are incompletely understood. Identifying correlates in patient tumor samples is challenging because of genetic and...
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, providing remarkable clinical responses in some patients. However, the majority of patients do not respond. It is therefore crucial both to identify predictive biomarkers of response and to increase the response rates to immune checkpoint therapy. In this review we explore the cu...
Cancer immunotherapy using antibodies that target immune checkpoints has delivered outstanding results. However, responses only occur in a subset of patients, and it is not fully understood what biological processes determine an effective outcome. This lack of understanding hinders the development of rational combination treatments. We set out to d...
Dexamethasone is a synthetic glucocorticoid commonly used for the prevention and management of side effects in cancer patients undergoing chemotherapy. While it is effective as an anti-emetic and in preventing hypersensitivity reactions, dexamethasone depletes peripheral blood lymphocytes and impacts immune responses. The effect of dexamethasone on...
Objective
Pleural effusion (PE) is a common feature of malignant pleural mesothelioma. These effusions typically contain lymphocytes and malignant cells. We postulated that the PE would be a source of lymphocytes for analysis of tumor immune milieu. The aim of this study was to compare the phenotype and T cell receptor usage of pleural effusion T c...
Exercise medicine is a relatively new but exciting field in cancer care. There is substantial evidence that exercise can reduce the risk of many cancers and improve survival in some cancers, including mesothelioma. Exercise during and after conventional therapies has been shown to be safe, improve symptom control, quality of life (QOL) and fitness,...
Mesothelioma is an aggressive asbestos induced cancer with extremely poor prognosis and limited treatment options. Immune checkpoint blockade (ICPB) has demonstrated effective therapy in melanoma and is now being applied to other cancers, including mesothelioma. However, the efficacy of ICPB and which immune checkpoint combinations constitute the b...
Objectives: Asbestos comprises six naturally occurring silicate minerals which have the common characteristic of being long (roughly 1:20 aspect ratio), thin fibrous crystals, with each visible fibre composed of millions of microscopic 'fibrils' that can be released by abrasion and other processes. Additionally, there are other non-asbestos mineral...
Background
Cytotoxic chemotherapeutics form the cornerstone of systemic treatment of many cancers. Patients are dosed at maximum tolerated dose (MTD), which is carefully determined in phase I studies. In contrast, in murine studies, dosages are often based on customary practice or small pilot studies, which often are not well documented. Consequent...
Background
CD40 signalling can synergise with chemotherapy in preclinical cancer models, and early clinical studies are promising. We set out to define the immunological changes associated with this therapeutic combination to identify biomarkers for a response to the therapy. Here, we present serial immunomonitoring examining dendritic cell and T c...
Neoadjuvant (preoperative) chemoradiotherapy (CRT) decreases the risk of rectal cancer recurrence and reduces tumour volume prior to surgery. However, response to CRT varies considerably between individuals and factors associated with response are poorly understood. Foxp3+ regulatory T cells (Tregs) inhibit anti-tumour immunity and may limit any re...
Recently, there has been a coordinated effort from academic institutions and the pharmaceutical industry to identify biomarkers that can predict responses to immune checkpoint blockade in cancer. Several biomarkers have been identified; however, none has reliably predicted response in a sufficiently rigorous manner for routine use. Here, we argue t...
Malignant mesothelioma (MM) is an aggressive serosal tumor associated with asbestos exposure. We previously demonstrated that mesothelial cells differentiate into cells of different mesenchymal lineages and hypothesize that osseous tissue observed in a subset of MM patients is due to local differentiation of MM cells. In this study, the capacity of...
Introduction
Regulatory T cells (Treg) play an important role in suppressing anti‐ immunity and their depletion has been linked to improved outcomes. To better understand the role of Treg in limiting the efficacy of anti‐cancer immunity, we used a Diphtheria toxin (DTX) transgenic mouse model to specifically target and deplete Treg.
Methods
Tumor...
Cancer immunotherapy, and in particular checkpoint blockade, is now standard clinical care for a growing number of cancers. Cytotoxic drugs have been the primary weapon against cancer for a long time and have typically been understood because of their capacity to directly kill tumour cells. It is now clear that these drugs are potential partners fo...
Introduction:
Malignant pleural mesothelioma (MPM) is a rare cancer with a heterogeneous prognosis. Prognostic models are not widely utilised clinically. Classification and regression tree (CART) analysis examines the interaction of multiple variables with a given outcome.
Methods:
Between 2005-2014, all cases with pathologically confirmed MPM h...
Background
The MexTAg transgenic mouse model of mesothelioma replicates many aspects of human mesothelioma, including induction by asbestos, pathogenicity and response to cytotoxic chemotherapy, despite high levels of the SV40 large T Antigen (TAg) in the mesothelial compartment. This model enables analysis of the molecular events associated with a...
Background:
Foxp3(+) regulatory T cells (Tregs) play a vital role in preventing autoimmunity, but also suppress antitumour immune responses. Tumour infiltration by Tregs has strong prognostic significance in colorectal cancer, and accumulating evidence suggests that chemotherapy and radiotherapy efficacy has an immune-mediated component. Whether T...
Objectives:
The immune effects of EGFR tyrosine kinase inhibitors (EGFR-TKIs) are poorly understood. Identifying immune biomarkers could guide patient selection and optimisation of EGFR-TKI-immunotherapy combinations.
Materials and methods:
33 patients with NSCLC treated with an EGFR-TKI were prospectively enrolled. Peripheral blood mononuclear...
Malignant pleural mesothelioma is an aggressive, treatment-resistant tumor, which continues to increase in frequency throughout the world because the causative agent, asbestos, has high economic importance, particularly in developing countries. Patients typically present with breathlessness and chest pain with pleural effusions. Median survival is...
Background: The immune effects of EGFRi are not well understood. Anti-
PD-1 immune checkpoint blockade was the first immunotherapy approved
in NSCLC. Identifying immune biomarkers predicting response could
guide patient selection and optimisation of therapeutic sequencing and
immunotherapy–EGFRi combinations.
Methods: Patients with advanced NSCLC t...
Background:
Data from murine models suggests that CD40 activation may synergise with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40 activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MP...
The glucocorticoid steroid dexamethasone is used as a supportive care co-medication for cancer patients undergoing standard care pemetrexed/platinum doublet chemotherapy. As trials for new cancer immunotherapy treatments increase in prevalence, it is important to track the immunological changes induced by co-medications commonly used in the clinic,...
Cancer immunotherapy has shown impressive results, but most patients do not respond. We hypothesized that the effector response in the tumour could be visualized as a complex network of interacting gene products and that by mapping this network we could predict effective pharmacological interventions. Here, we provide proof of concept for the valid...
A key to improving cancer immunotherapy will be the identification of tumor-specific ‘neo-antigens’ that arise from mutations and augmenting the resultant host immune response. In this study we identified single nucleotide variants (SNV) from RNA sequencing of asbestos induced murine mesothelioma cell lines, AB1 and AB1-HA. Using the NetMHCpan 2.8...
Tumor antigen cross-presentation by dendritic cells (DCs) to specific CD8+ T cells is central to antitumor immunity. Although highly efficient in draining lymph nodes, it is defective within the tumor site itself. Importantly, an immunogenic chemotherapy, gemcitabine, reverses this defect, allowing the potential re-stimulation of cytotoxic T lympho...
Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment for many solid malignancies. Although this approach can be effective, it often has limited success against recurrent or metastatic cancers and new multimodality approaches are needed. Adjuvant immunotherapy is another potentially effective approach. We...
Given the impressive efficacy of immune checkpoint blockade in thoracic malignancies, and the recently discovered immune-stimulating properties of many cytotoxic drugs, a logical next step would be to combine these treatments. However, the rational design of clinical trials investigating these combinations is hampered by a lack of knowledge regardi...
Targeted depletion of regulatory T cells is important for effective adjuvant immunotherapy of murine mesothelioma
Scott A Fisher1,2,*, Andrea Khong1,2, Wayne Aston1,2, Justin Simms1,2, Thomas Casey1,2, Bruce W. Robinson1,2, W. Joost Lesterhuis1,2 , Richard A. Lake1,2
1National Centre for Asbestos Related Diseases (NCARD), Perth, Australia.
2Schoo...
Objectives
Non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors have been associated with lower incidence rates of some cancers. Because asbestos can cause chronic inflammation at the pleural and peritoneal surfaces we hypothesised that NSAID and COX-2 inhibitors would inhibit the development of asbestos-induced mesothelioma.
Materi...
Cross-presentation defines the unique capacity of an antigen presenting cell to present exogenous antigen via MHC class I molecules to CD8+ T cells. Dendritic cells (DCs) are specialized cross-presenting cells and as such have a critical role in anti-tumor immunity. DCs are routinely found within the tumor microenvironment, but their capacity for e...
Mouse models of cancer are invaluable for obtaining detailed knowledge
about tumor development and for screening therapeutic and preventive approaches.
Mesothelioma is an unusual cancer because the same carcinogen, asbestos, causes a similar
disease in both humans and animals. Unlike most other cancers, murine mesothelioma can
therefore be regarded...
Cross-presentation of tumor antigen is essential for efficient priming of nave CD8 + T lymphocytes and induction of effective anti-tumor immunity. We hypothesized that the subcellular location of a tumor antigen could affect the efficiency of cross-presentation, and hence the outcome of anti-tumor responses to that antigen. We compared cross-presen...
Background
This study was conducted to determine if anti-tumor vaccination administered prior to partial debulking surgery could improve survival using a murine solid tumour model.Methods
Tumor incidence and survival rates were compared in mice bearing subcutaneous AB1-HA mesothelioma tumors that received either sham surgery, debulking surgery or v...