Distinct Molecular Mechanisms of Altered HLA Class II Expression in Malignant Melanoma.

Background: The human leukocyte antigen (HLA) class II molecules are constitutively expressed in some melanoma, but the underlying molecular mechanisms have not yet been characterized.

Methods: The expression of HLA class II antigen processing machinery (APM) components was determined in melanoma samples by qPCR, Western blot, flow cytometry and immunohistochemistry. Immunohistochemical and TCGA datasets were used for correlation of HLA class II expression to tumor grading, T-cell infiltration and patients' survival.

Tumor Microenvironment, HLA Class I and APM Expression in HPV-Negative Oral Squamous Cell Carcinoma.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study, the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN-γ signaling and to the patient's outcome. A heterogeneous but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells.

Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy.

Immunotherapy aims to activate the immune system to fight cancer in a very specific and targeted manner. Despite the success of different immunotherapeutic strategies, in particular antibodies directed against checkpoints as well as adoptive T-cell therapy, the response of patients is limited in different types of cancers. This attributes to escape of the tumor from immune surveillance and development of acquired resistances during therapy.

TGF-β inducible epithelial-to-mesenchymal transition in renal cell carcinoma.

Epithelial-to-mesenchymal transition (EMT) is a crucial step in cancer progression and the number one reason for poor prognosis and worse overall survival of patients. Although this essential process has been widely studied in many solid tumors as e.g.

Correction to: Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma.

The original version of this article [1], published on 5 April 2016, contains a mistake. In the 'Role of pH stabilisation' section, "intracellular pH" has been incorrectly abbreviated as "pHe". The correct abbreviation is "pHi".

Multiparametric immune profiling in HPV- oral squamous cell cancer.

Evaluation of T lymphocyte frequency provides prognostic information for patients with oral squamous cell cancer (OSCC). However, the effect of simultaneously evaluating T cell frequency and assessing suppressive elements and defects in antigen-processing machinery (APM) has not been clarified. Simultaneous characterization of CD3+, CD8+, FoxP3+, CD163+, and PD-L1+ cells using multispectral imaging was performed on sections from 119 patients with HPV- OSCC.

Modulation of MHC class I surface expression in B16F10 melanoma cells by methylseleninic acid.

The essential trace element selenium (Se) might play a role in cancer prevention as well as for cancer therapy. Its metabolite methylselenol is able to kill cells through distinct mechanisms including induction of reactive oxygen species, DNA damage and apoptosis. Since methylselenol affects innate immune responses by modulating the expression of NKG2D ligands, the aim of this study was to determine whether the methylselenol generating compound methylseleninic acid (MSA) influences the expression of the MHC class I surface antigens and growth properties thereby reverting immune escape.

HLA-E expression and its clinical relevance in human renal cell carcinoma.

The non-classical human leukocyte antigen E (HLA-E) expression is frequently overexpressed in tumor diseases, transplants and virus-infected cells and represents an immunomodulatory molecule by binding to the receptors CD94/NKG2A, -B and -C on NK and T cells. Due to its immune suppressive features HLA-E expression might represent an important mechanism of tumors to escape immune surveillance.While an aberrant expression of the non-classical HLA-G antigen in human renal cell carcinoma (RCC) has been demonstrated to be associated with a worse outcome of patients and reduced sensitivity to immune effector cell-mediated cytotoxicity, the expression and function of HLA-E has not yet been analyzed in this tumor entity.

Clinical relevance of the tumor microenvironment and immune escape of oral squamous cell carcinoma.

Background: Changes in the tumor microenvironment and immune surveillance represent crucial hallmarks of various kinds of cancer, including oral squamous cell carcinoma (OSCC), and a close crosstalk of hypoxia regulating genes, an activation of chemokines and immune cells has been described.

Methods: A review about the pivotal role of HIF-1, its crosstalk to various cornerstones in OSCC tumorigenesis is presented.

Results: Hypoxia is a frequent event in OSCC and leads to a reprogramming of the cellular metabolism in order to prevent cell death.

Clinical relevance of miR-mediated HLA-G regulation and the associated immune cell infiltration in renal cell carcinoma.

In human tumors of distinct origin including renal cell carcinoma (RCC), the non-classical human leukocyte antigen G (HLA-G) is frequently expressed, thereby inhibiting the cytotoxic activity of T and natural killer (NK) cells. Recent studies demonstrated a strong post-transcriptional gene regulation of the HLA-G by miR-152, -148A, -148B and -133A. Standard methods were applied to characterize the expression and function of HLA-G, HLA-G-regulatory microRNAs (miRs) and the immune cell infiltration in 453 RCC lesions using a tissue microarray and five RCC cell lines linking these results to clinical parameters.

HER-2/neu mediates oncogenic transformation via altered CREB expression and function.

Unlabelled: The cyclic (c)AMP responsive element binding protein (CREB) plays a key role in many cellular processes, including differentiation, proliferation, and signal transduction. Furthermore, CREB overexpression was found in tumors of distinct origin and evidence suggests an association with tumorigenicity. To establish a mechanistic link between HER-2/neu-mediated transformation and CREB protein expression and function, in vitro models of HER-2/neu-overexpressing and HER-2/neu-negative/silenced counterparts as well as human mammary carcinoma lesions with defined HER-2/neu status were used.

The role of classical and non-classical HLA class I antigens in human tumors.

In human tumors alterations in the surface expression and/or function of the major histocompatibility complex (MHC) class I antigens are frequently found and equip neoplastic cells with mechanisms to escape immune control. The aberrant expression of HLA class I molecules can be caused by structural alterations or dysregulations of genes encoding the classical HLA class I antigens and/or components of the HLA class I antigen processing machinery (APM). The dysregulation of APM components could occur at the epigenetic, transcriptional or post-transcriptional level.

Identification and characterization of human leukocyte antigen class I ligands in renal cell carcinoma cells.

The presentation of tumor antigen-derived peptides by human leukocyte antigen (HLA) class I surface antigens on tumor cells is a key prerequisite to trigger effective T-cell responses in cancer patients. Multiple complementary strategies like cDNA and serological expression cloning, reverse immunology and different 'ome'-based methods have been employed to identify potential T-cell targets. This report focuses on a ligandomic profiling approach leading to the identification of 49 naturally processed HLA class I peptide ligands presented on the cell surface of renal cell carcinoma (RCC) cells.

Association of IFN-gamma signal transduction defects with impaired HLA class I antigen processing in melanoma cell lines.

Purpose: Abnormalities in the constitutive and IFN-γ-inducible HLA class I surface antigen expression of tumor cells is often associated with an impaired expression of components of the antigen processing machinery (APM). Hence, we analyzed whether there exists a link between the IFN-γ signaling pathway, constitutive HLA class I APM component expression, and IFN-γ resistance.

Experimental Design: The basal and IFN-γ-inducible expression profiles of HLA class I APM and IFN-γ signal transduction cascade components were assessed in melanoma cells by real-time PCR (RT-PCR), Western blot analysis and/or flow cytometry, the integrity of the Janus activated kinase (JAK) 2 locus by comparative genomic hybridization.

Identification of E2F1 as an important transcription factor for the regulation of tapasin expression.

HER-2/neu overexpression in tumor cells caused abnormalities of MHC class I surface expression due to impaired expression of components of the antigen-processing machinery (APM) including the low molecular weight proteins, the transporter associated with antigen processing (TAP), and the chaperone tapasin, whereas the expression of MHC class I heavy chain as well as β(2)-microglobulin was only marginally affected. This oncogene-mediated deficient APM component expression could be reverted by interferon-γ treatment, suggesting a deregulation rather than structural alterations as underlying molecular mechanisms. To determine the level of regulation, the transcriptional activity of APM components was analyzed in HER-2/neu(-) and HER-2/neu(+) cells.

Epigenetic control of the ubiquitin carboxyl terminal hydrolase 1 in renal cell carcinoma.

Background: The ubiquitin carboxyl-terminal hydrolase 1 (UCHL1) gene involved in the regulation of cellular ubiquitin levels plays an important role in different cellular processes including cell growth and differentiation. Aberrant expression of UCHL1 has been found in a number of human solid tumors including renal cell carcinoma (RCC). In RCC, UCHL1 overexpression is associated with tumor progression and an altered von Hippel Lindau gene expression.

Expression and regulation of non-classical HLA-G in renal cell carcinoma.

Under physiological conditions, the non-classical major histocompatibility complex class Ib molecule human leukocyte antigen G (HLA-G) is selectively expressed in placental trophoblasts, thymus and cornea. In pathological situations, HLA-G expression was frequently found in tumour cells of distinct origin, thereby allowing these tumour cells to escape immune surveillance. Although HLA-G expression occurs at a relatively high frequency in renal cell carcinoma (RCC) of the clear cell subtype, the molecular mechanisms of its aberrant expression in RCC has not yet been determined.

Identification of fatty acid binding proteins as markers associated with the initiation and/or progression of renal cell carcinoma.

Renal cell carcinoma (RCC) representing the most common neoplasia of the kidney in Western countries is a histologic diverse disease with an often unpredictable course. The prognosis of RCC is worsened with the onset of metastasis, and the therapies currently available are of limited success for the treatment of metastatic RCC. Although gene expression analyses and other methods are promising tools clarifying and standardizing the pathological classification of RCC, novel innovative molecular markers for the diagnosis, prognosis, and for the monitoring of this disease during therapy as well as potential therapeutic targets are urgently needed.

Ontogeny and oncogenesis balance the transcriptional profile of renal cell cancer.

Global transcript analysis is increasingly used to describe cancer taxonomies beyond the microscopic reach of the eye. Diagnostic and prognostic portraits are formulated by ranking cancers according to transcriptional proximity. However, the role that distinct biological factors play in defining these portraits remains undefined.

The role of HLA-G for protection of human renal cell-carcinoma cells from immune-mediated lysis: implications for immunotherapies.

HLA-G as a non-classical MHC class I molecule exhibits a limited tissue distribution and exerts multiple immune regulatory functions including the induction of immune tolerance. In addition, HLA-G has been detected in some tumors of different histology and therefore may represent a novel immune escape mechanism of tumor cells. Despite the immunogenicity of renal cell carcinoma (RCC), outgrowth of tumor cells occurs which might be attributable to abrogation of efficient anti-tumor responses.

Altered expression of nonclassical HLA class Ib antigens in human renal cell carcinoma and its association with impaired immune response.

An optimal antitumoral immune response requires the activation of both CD8(+) and CD4(+) T lymphocytes by the peptide antigen presentation via the human leukocyte antigen (HLA) class I and class II molecules, respectively. Downregulation or loss of HLA molecules has been found in human renal cell carcinoma (RCC) and provides a strategy of these tumors to evade T-cell mediated immunosurveillance. In addition, a tumor-specific upregulation of HLA-G has been recently described in RCC, which also leads to an impaired immune response.

Functional role of human leukocyte antigen-G up-regulation in renal cell carcinoma.

The nonclassical HLA-G molecule exhibits a limited tissue distribution and exerts multiple immune regulatory functions. Recent studies indicate that HLA-G expression plays a key role in the induction of immune tolerance and may represent a novel immune escape mechanism of tumor cells. Despite a high frequency of tumor-infiltrating T lymphocytes in renal cell carcinoma (RCC) lesions, outgrowth of tumor cells occurs that might be attributable to abrogation-efficient antitumor responses.

Identification of markers for the selection of patients undergoing renal cell carcinoma-specific immunotherapy.

Renal cell carcinoma (RCC) represents the most common malignant tumor in the kidney and is resistant to conventional therapies. The diagnosis of RCC is often delayed leading to progression and metastatic spread of the disease. Thus, validated markers for the early detection of the disease as well as selection of patients undergoing specific therapy is urgently needed.

Identification of metabolic enzymes in renal cell carcinoma utilizing PROTEOMEX analyses.

PROTEOMEX, an approach which combines conventional proteome analysis with serological screening, is a powerful tool to separate proteins and identify immunogenic components in malignant diseases. By applying this approach, we characterized nine metabolic enzymes which were differentially expressed in renal cell carcinoma (RCC) cell lines and compared their expression profiles to that of normal kidney epithelium cells. Four of these proteins, superoxide dismutase (SODC), triosephosphatase isomerase (TPIS), thioredoxin (THIO) and ubiquitin carboxyl-terminal hydrolase (UBL1) were further analysed for both their constitutive and interferon (IFN)-gamma inducible protein expression pattern in cell lines or tissue specimens derived from RCC or normal kidney epithelium using Western blot analysis and immunohistochemistry, respectively.