[Show abstract][Hide abstract] ABSTRACT: High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This 'roadmap' for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015.
Full-text · Article · Oct 2015 · Nature reviews. Cancer
[Show abstract][Hide abstract] ABSTRACT: Tumor barriers preventing T cell homing and engraftment should be neutralized during cancer immunotherapy. We recently found that ovarian cancer expresses quasi-universal chemokines that can support T cell homing, and T cells elicited by whole tumor antigen dendritic-cell vaccines express the cognate chemokine receptors, which are upregulated by CD3/CD28 costimulation.
[Show abstract][Hide abstract] ABSTRACT: The discovery of long non-coding RNA (lncRNA) has dramatically altered our understanding of cancer. Here, we describe a comprehensive analysis of lncRNA alterations at transcriptional, genomic, and epigenetic levels in 5,037 human tumor specimens across 13 cancer types from The Cancer Genome Atlas. Our results suggest that the expression and dysregulation of lncRNAs are highly cancer type specific compared with protein-coding genes. Using the integrative data generated by this analysis, we present a clinically guided small interfering RNA screening strategy and a co-expression analysis approach to identify cancer driver lncRNAs and predict their functions. This provides a resource for investigating lncRNAs in cancer and lays the groundwork for the development of new diagnostics and treatments.
[Show abstract][Hide abstract] ABSTRACT: Infiltration of cytotoxic T-lymphocytes in ovarian cancer is a favorable prognostic factor. Employing a differential expression approach, we have recently identified a number of genes associated with CD8+ T-cell infiltration in early stage ovarian tumors. In the present study, we validated by qPCR the expression of two genes encoding the transmembrane proteins GPC6 and TMEM132D in a cohort of early stage ovarian cancer patients. The expression of both genes correlated positively with the mRNA levels of
, a marker of T-lymphocyte infiltration [Pearson coefficient: 0.427 (
) and 0.861 (
expression was also documented in a variety of ovarian cancer cell lines. Importantly, Kaplan-Meier survival analysis revealed that high mRNA levels of GPC6 and/or TMEM132D correlated significantly with increased overall survival of early stage ovarian cancer patients
may serve as predictors of CD8+ T-lymphocyte infiltration and as favorable prognostic markers in early stage ovarian cancer with important consequences for diagnosis, prognosis, and tumor immunobattling.
[Show abstract][Hide abstract] ABSTRACT: With its vast amount of uncharacterized and characterized T cell epitopes available for activating CD4⁺ T helper and CD8⁺ cytotoxic lymphocytes simultaneously, whole tumor antigen represents an attractive alternative source of antigens as compared to tumor-derived peptides and full-length recombinant tumor proteins for dendritic cell (DC)-based immunotherapy. Unlike defined tumor-derived peptides and proteins, whole tumor lysate therapy is applicable to all patients regardless of their HLA type. DCs are essentially the master regulators of immune response, and are the most potent antigen-presenting cell population for priming and activating naïve T cells to target tumors. Because of these unique properties, numerous DC-based immunotherapies have been initiated in the clinics. In this review, we describe the different types of whole tumor antigens that we could use to pulse DCs ex vivo and in vivo. We also discuss the different routes of delivering whole tumor antigens to DCs in vivo and activating them with toll-like receptor agonists.
[Show abstract][Hide abstract] ABSTRACT: In immune intervention trials, the comprehensive investigation of immunogenicity or T-cell epitope-mapping is challenging especially when a large set of epitopes needs to be screened and limited sample material is available. To this end, T-cell responses are often monitored using peptide pools. Here, we assessed the magnitude and sensitivity of detection of antigen-specific CD8 and CD4 T-cells using a single peptide alone or mixed into large pools. Interestingly the magnitude of ex-vivo anti-viral and anti-tumor T cell-responses was identical irrespective of the presence and number of irrelevant peptides, in different functional assays with PBMCs from healthy donors and cancer patients. Moreover, the presence of up to 300 irrelevant peptides did not affect the threshold of responsiveness of antigen-specific CD8 T-cells to single cognate peptides. These data demonstrate the relevance of using very large peptide pools for the sensitive and specific immune-monitoring of epitope-specific T-cells in natural or immune-modulated context.
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention.
In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches.
Firstly, we show that, in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM.
In conclusion, inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer.
Full-text · Article · Mar 2015 · PLoS Computational Biology
[Show abstract][Hide abstract] ABSTRACT: Effective treatment of ovarian cancer depends upon the early detection of the malignancy. Here, we report on the development of a new nanostructured immunosensor for early detection of cancer antigen 125 (CA-125). Gold electrode was modified with mercaptopropionic acid (MPA), then consecutively conjugated with silica coated gold nanoparticles (AuNPs@SiO 2), CdSe quantum dots (QDs) and anti CA-125 monoclonal antibody (mAb). The engineered MPA|AuNPs@SiO 2 |QD|mAb immunosensor was characterised using transmission electron microscopy (TEM), atomic force microscopy (AFM), cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). Successive conjugation of AuNPs@SiO 2 , CdSe QD and anti CA-125 mAb onto the gold electrode resulted in sensitive detection of CA-125 with a limit of detection (LOD) of 0.0016 U/mL and linear detection range (LDR) of 0-0.1 U/mL. Based on the high sensitivity and specificity of the immunosensor, we propose this highly stable and reproducible biosensor for the early detection of CA-125 of the disease.
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Dendritic cells (DCs) are the most important antigen-presenting cell population for activating antitumor T-cell responses; therefore, they offer a unique opportunity for specific targeting of tumors.
We will discuss the critical factors for the enhancement of DC vaccine efficacy: different DC subsets, types of in vitro DC manufacturing protocol, types of tumor antigen to be loaded and finally different adjuvants for activating them. We will cover potential combinatorial strategies with immunomodulatory therapies: depleting T-regulatory (Treg) cells, blocking VEGF and blocking inhibitory signals. Furthermore, recommendations to incorporate these criteria into DC-based tumor immunotherapy will be suggested.
Monocyte-derived DCs are the most widely used DC subset in the clinic, whereas Langerhans cells and plasmacytoid DCs are two emerging DC subsets that are highly effective in eliciting cytotoxic T lymphocyte responses. Depending on the type of tumor antigens selected for loading DCs, it is important to optimize a protocol that will generate highly potent DCs. The future aim of DC-based immunotherapy is to combine it with one or more immunomodulatory therapies, for example, Treg cell depletion, VEGF blockage and T-cell checkpoint blockage, to elicit the most optimal antitumor immunity to induce long-term remission or even cure cancer patients.
No preview · Article · Jan 2015 · Expert Opinion on Biological Therapy
[Show abstract][Hide abstract] ABSTRACT: Phage display technology (PDT), a combinatorial screening approach, provides a molecular diversity tool for creating libraries of peptides/proteins and discovery of new recombinant therapeutics. Expression of proteins such as monoclonal antibodies (mAbs) on the surface of filamentous phage can permit the selection of high affinity and specificity therapeutic mAbs against virtually any target antigen. Using a number of diverse selection platforms (e.g. solid phase, solution phase, whole cell and in vivo biopannings), phage antibody libraries (PALs) from the start point provides great potential for the isolation of functional mAb fragments with diagnostic and/or therapeutic purposes. Given the pivotal role of PDT in the discovery of novel therapeutic/diagnostic mAbs, in the current review, we provide an overview on PALs and discuss their impact in the advancement of engineered mAbs.
No preview · Article · Nov 2014 · Critical Reviews in Biotechnology
[Show abstract][Hide abstract] ABSTRACT: Aberrant blood vessels enable tumor growth, provide a barrier to immune infiltration, and serve as a source of pro-tumorigenic signals. Targeting tumor blood vessels for destruction, or tumor vascular disruption therapy, can therefore provide significant therapeutic benefit. Here we describe the ability of chimeric antigen receptor (CAR) bearing T cells to recognize human PSMA (hPSMA) on endothelial targets in vitro as well as in vivo. CAR T cells were generated using the anti-PSMA scFv, J591, and the intracellular signaling domains: CD3 zeta, CD28, and/or CD137/4-1BB. We found that all anti-hPSMA CAR T cells recognized and eliminated PSMA+ endothelial targets in vitro, regardless of signaling domain. T cells bearing the 3rd generation anti-hPSMA CAR, P28BBζ, were able to recognize and kill primary human endothelial cells isolated from gynecological cancers. In addition, the P28BBζ CAR T cells mediated regression of hPSMA-expressing vascular neoplasms in mice. Finally, in murine ovarian cancers models populated by murine vessels expressing hPSMA, the P28BBζ CAR T cells were able to ablate PSMA+ vessels, cause secondary depletion of tumor cells, and reduce tumor burden. Taken together, these results provide strong rationale for the use of CAR T cells as agents of tumor vascular disruption, specifically those targeting PSMA.