Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma.

Background: Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials.

Methods: We analysed somatic mutations from 229 MPM samples, including previously published data and 58 samples that had undergone WGS within this study.

Comprehensive Testing of Chemotherapy and Immune Checkpoint Blockade in Preclinical Cancer Models Identifies Additive Combinations.

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 checkpoint blockade (ICB).

BAP1 Loss by Immunohistochemistry Predicts Improved Survival to First-Line Platinum and Pemetrexed Chemotherapy for Patients With Pleural Mesothelioma: A Validation Study.

Introduction: Pleural mesothelioma (PM) is an aggressive malignancy with no identified predictive biomarkers. We assessed whether tumor BAP1 status is a predictive biomarker for survival in patients receiving first-line combination platinum and pemetrexed therapy.

Methods: PM cases (n = 114) from Aalborg, Denmark, were stained for BAP1 on tissue microarrays.

What's next in cancer immunotherapy? - The promise and challenges of neoantigen vaccination.

The process of tumorigenesis leaves a series of indelible genetic changes in tumor cells, that when expressed, have the potential to be tumor-specific immune targets. Neoantigen vaccines that capitalize on this potential immunogenicity have shown efficacy in preclinical models and have now entered clinical trials. Here we discuss the status of personalized neoantigen vaccines and the current major challenges to this nascent field.

Neutrophil-to-lymphocyte ratio in malignant pleural fluid: Prognostic significance.

Predicting survival of patients with malignant pleural effusions (MPEs) is notoriously difficult. A robust prognostic marker can guide clinical decision making. The neutrophil-to-lymphocyte ratio (NLR) in blood has been shown to predict survival in many cancers.

Tumor Infiltrating Effector Memory Antigen-Specific CD8 T Cells Predict Response to Immune Checkpoint Therapy.

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 tumor models with dichotomous responses to ICT.

Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome.

Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.

Identification of a CD8+ T-cell response to a predicted neoantigen in malignant mesothelioma.

Neoantigens present unique and specific targets for personalized cancer immunotherapy strategies. Given the low mutational burden yet immunotherapy responsiveness of malignant mesothelioma (MM) when compared to other carcinogen-induced malignancies, identifying candidate neoantigens and T cells that recognize them has been a challenge. We used pleural effusions to gain access to MM tumor cells as well as immune cells in order to characterize the tumor-immune interface in MM.

Combination immune checkpoint blockade as an effective therapy for mesothelioma.

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 best therapeutic option for mesothelioma have yet to be fully elucidated.

Whole exome sequencing of an asbestos-induced wild-type murine model of malignant mesothelioma.

Background: Malignant mesothelioma (MM) is an aggressive cancer of the pleural and peritoneal cavities caused by exposure to asbestos. Asbestos-induced mesotheliomas in wild-type mice have been used extensively as a preclinical model because they are phenotypically identical to their human counterpart. However, it is not known if the genetic lesions in these mice tumours are similar to in the human disease, a prerequisite for any new preclinical studies that target genetic abnormalities.

A Proteomic Analysis of the Malignant Mesothelioma Secretome Using iTRAQ.

Unlabelled: Backgound/Aim: Malignant mesothelioma (MM) is an aggressive and fatal pleural cancer. The cell secretome offers information allowing insight into the pathogenesis of MM while offering the possibility to identify potential therapeutic targets and biomarkers. In the present study the secretome protein profile of MM cell lines was compared to normal mesothelial cells.

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.

Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis.

Immune response profiling of malignant pleural mesothelioma for diagnostic and prognostic biomarkers.

The asbestos induced cancer malignant mesothelioma (MM) is difficult to diagnose and has a poor prognosis. MM is an immunological cancer, therefore autoantibodies may be suitable biomarkers and associated with prognosis. We used Protoarray(®) microarrays to determine immune responses to 8798 antigens in 10 MM and 10 asbestos exposed controls and developed diagnostic panels using 17 antigens from this.

Consistent gene expression profiles in MexTAg transgenic mouse and wild type mouse asbestos-induced mesothelioma.

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 asbestos induced mesothelioma and is utilised here to investigate the molecular dynamics of tumours induced in these mice, using gene expression patterns as a read out.

Methods: Gene expression of MexTAg mesothelioma cell lines bearing a high or low number of copies of the TAg transgene were compared to wild type mouse mesotheliomas and normal mouse mesothelial cells using Affymetrix microarray.

Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations.

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 validity of this approach in a murine mesothelioma model, which displays a dichotomous response to anti-CTLA4 immune checkpoint blockade.

Strong spontaneous tumor neoantigen responses induced by a natural human carcinogen.

A key to improving cancer immunotherapy will be the identification of tumor-specific "neoantigens" that arise from mutations and augment the resultant host immune response. In this study we identified single nucleotide variants (SNVs) by RNA sequencing of asbestos-induced murine mesothelioma cell lines AB1 and AB1-HA. Using the NetMHCpan 2.

Comparison of mesothelin and fibulin-3 in pleural fluid and serum as markers in malignant mesothelioma.

Purpose Of Review: Malignant mesothelioma is an asbestos-induced, aggressive tumour, which frequently presents with pleural effusion. There are over 60 reported causes that can result in the development of a pleural effusion. Currently, there are no tumour biomarkers in widespread clinical use for the differential diagnosis of mesothelioma from other diseases.

Discovery of new biomarkers for malignant mesothelioma.

Malignant mesothelioma is an asbestos-induced, aggressive tumour with limited treatment options and very poor outcome. Currently, there are no tumour biomarkers in widespread clinical use for this disease. Soluble mesothelin is the most intensively investigated mesothelioma biomarker and has been approved by the US FDA primarily as a tool for monitoring patient response and progression.

Absence of germline mutations in BAP1 in sporadic cases of malignant mesothelioma.

Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed individuals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility.

Pleural fluid mesothelin as an adjunct to the diagnosis of pleural malignant mesothelioma.

Rationale: The diagnosis of pleural malignant mesothelioma (MM) by effusion cytology may be difficult and is currently controversial. Effusion mesothelin levels are increased in patients with MM but the clinical role of this test is uncertain.

Objectives: To determine the clinical value of measuring mesothelin levels in pleural effusion supernatant to aid diagnosis of MM.

Comparison of fibulin-3 and mesothelin as markers in malignant mesothelioma.

Background: Pleural malignant mesothelioma (MM) is a deadly tumour predominantly associated with asbestos exposure. A reliable diagnostic and prognostic marker for MM will significantly enhance clinical care and is an area of intense research. Soluble mesothelin is the most studied and an FDA-approved biomarker for MM.

Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum.

The MSLN gene products, soluble mesothelin and megakaryocyte potentiating factor (MPF), are being investigated as biomarkers for the asbestos-related cancer malignant mesothelioma (MM). Pleural fluid biomarkers of MM can be elevated when serum levels remain normal. The aim of this study was to determine if this was true for MPF and to compare levels of mesothelin.

Pleural effusion hyaluronic acid as a prognostic marker in pleural malignant mesothelioma.

Background: Malignant mesothelioma (MM), a primarily asbestos-induced tumour, has a poor prognosis, with over-all 5-year survival less than 5%. Tumour biomarkers are being intensely investigated in MM as aids to diagnosis and prognosis. Hyaluronic acid (HA) is produced in MM but its role in prognostication remains uncertain.

Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity.

Several chemotherapeutics exert immunomodulatory effects. One of these is the nucleoside analogue gemcitabine, which is widely used in patients with lung cancer, ovarian cancer, breast cancer, mesothelioma and several other types of cancer, but with limited efficacy. We hypothesized that the immunopotentiating effects of this drug are partly restrained by the inhibitory T cell molecule CTLA-4 and thus could be augmented by combining it with a blocking antibody against CTLA-4, which on its own has recently shown beneficial clinical effects in the treatment of patients with metastatic melanoma.

Does CA125 binding to mesothelin impact the detection of malignant mesothelioma?

The biomarker mesothelin is a useful diagnostic tool in malignant mesothelioma (MM) patients. It has high specificity but a sensitivity of only 50%. As mesothelin binds CA125, and as CA125 is often elevated in MM, we asked whether this binding affected measurable mesothelin levels in a relevant clinical setting.