scholarly journals MiRNAs Correlate with HLA Expression in Uveal Melanoma: Both Up- and Downregulation Are Related to Monosomy 3

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4020
Author(s):  
Zahra Souri ◽  
Annemijn P. A. Wierenga ◽  
Emine Kiliç ◽  
Erwin Brosens ◽  
Stefan Böhringer ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Uveal Melanoma ◽  
Immune Cell ◽  
Hla Class I ◽  
Class I ◽  
Chromosome 3 ◽  
Data Set ◽  
Monosomy 3 ◽  
Genetic Status ◽  
Infiltrating Lymphocytes

MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I expression and inflammation. We also determined whether such miRNAs were related to the UM’s genetic status. The expression of 125 miRNAs was determined in 64 primary UM from Leiden. Similarly, the mRNA expression of HLA-A, HLA-B, TAP1, BAP1, and immune cell markers was obtained. Expression levels of 24 of the 125 miRNAs correlated with expression of at least three out of four HLA Class I probes. Four miRNAs showed a positive correlation with HLA expression and infiltration with leukocytes, 20 a negative pattern. In the first group, high miRNA levels correlated with chromosome 3 loss/reduced BAP1 mRNA expression, in the second group low miRNA levels. The positive associations between miRNA-22 and miRNA-155 with HLA Class I were confirmed in the TCGA study and Rotterdam cohort, and with TAP1 in the Rotterdam data set; the negative associations between miRNA-125b2 and miRNA-211 and HLA-A, TAP1, and CD4 were confirmed in the Rotterdam set. We demonstrate two patterns: miRNAs can either be related to a high or a low HLA Class I/TAP1 expression and the presence of infiltrating lymphocytes and macrophages. However, both patterns were associated with chromosome 3/BAP1 status, which suggests a role for BAP1 loss in the regulation of HLA expression and inflammation in UM through miRNAs.

scholarly journals Loss of BAP1 Is Associated with Upregulation of the NFkB Pathway and Increased HLA Class I Expression in Uveal Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1102 ◽  
Author(s):  
Zahra Souri ◽  
Annemijn P. A. Wierenga ◽  
Christiaan van Weeghel ◽  
Pieter A. van der Velden ◽  
Wilma G. M. Kroes ◽  
...  
Keyword(s):  
T Cells ◽  
Uveal Melanoma ◽  
Immune Cells ◽  
Immunohistochemical Staining ◽  
Hla Class I ◽  
Class I ◽  
Monosomy 3 ◽  
Inflammatory Phenotype ◽  
Nfkb Pathway ◽  
Chromosome Status

One of the characteristics of prognostically infaust uveal melanoma (UM) is an inflammatory phenotype, which is characterized by high numbers of infiltrating T cells and macrophages, and a high HLA Class I expression. We wondered how this inflammation is regulated, and considered that one of the most important regulators of inflammation, the NFkB pathway, might play a role. We analyzed 64 UM samples for expression of HLA Class I, its regulators, and of members of the NFkB transcription family, using an Illumina HT12V4 array. HLA Class I expression and infiltrating immune cells were also determined by immunohistochemical staining. Information was obtained regarding chromosome status by Affymetrix Nsp array. Our analysis shows that expression of NFkB1, NFkB2 and RELB positively correlates with the level of HLA Class I expression and the number of infiltrating T cells and macrophages, while SPP1 and PPARγ are negatively correlated. Increased levels of NFkB1 and NFkB2 and decreased levels of SPP1 and PPARγ are seen in Monosomy 3/BAP1-negative tumors. This is also the case in non-inflammatory UM, indicating that our observation not only involves infiltrating leukocytes but the tumor cells themselves. We report that the NFkB pathway is associated with inflammation and HLA Class I expression in UM, and is upregulated when BAP1 expression is lost.

scholarly journals Soluble HLA in the Aqueous Humour of Uveal Melanoma Is Associated with Unfavourable Tumour Characteristics

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1202 ◽  
Author(s):  
Annemijn P. A. Wierenga ◽  
Gülçin Gezgin ◽  
Els van Beelen ◽  
Michael Eikmans ◽  
Marijke Spruyt-Gerritse ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Aqueous Humour ◽  
Immune Cell ◽  
Hla Class I ◽  
Luminex Assay ◽  
Monosomy 3 ◽  
Inflammatory Phenotype ◽  
Genetic Tumour ◽  
Soluble Hla ◽  
Tumour Characteristics

A high HLA expression in uveal melanoma (UM) is part of the prognostically unfavorable inflammatory phenotype. We wondered whether the presence of soluble HLA (sHLA) in the aqueous humour is associated with clinical, histopathological or genetic tumour characteristics, and represents tumour HLA expression and intratumoural inflammation. Aqueous humour from 108 UM patients was analysed for the presence of sHLA, using a Luminex assay specific for HLA Class I. Clinical and genetic parameters were compared between sHLA-positive and negative eyes. A qPCR analysis was performed on tumour tissue using a Fluidigm assay. In 19/108 UM-containing eyes, the sHLA level in the aqueous was above the detection limit. Tumours in sHLA-positive eyes were significantly larger, more frequently involved the ciliary body, and more often showed monosomy 3, gain of chromosome 8q and loss of BAP1 staining. Melanoma-related survival was worse in patients with sHLA-positive aqueous humour. sHLA in the aqueous did not represent the tumour’s HLA expression and did not relate to immune cell infiltration in the tumour. We conclude that UM-containing eyes may contain sHLA in the aqueous humour, where it is a prognostically-unfavourable sign and may influence local immune responses.

scholarly journals Do GNAQ and GNA11 Differentially Affect Inflammation and HLA Expression in Uveal Melanoma?

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1127 ◽  
Author(s):  
Christiaan van Weeghel ◽  
Annemijn P. A. Wierenga ◽  
Mieke Versluis ◽  
Thorbald van Hall ◽  
Pieter A. van der Velden ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Hla Class I ◽  
Class I ◽  
Chromosome 3 ◽  
Snp Analysis ◽  
Single Nucleotide ◽  
Main Determinant ◽  
Kaplan Meier ◽  
The Difference

Inflammation, characterized by high numbers of infiltrating leukocytes and a high HLA Class I expression, is associated with a bad prognosis in uveal melanoma (UM). We wondered whether mutations in GNA11 or GNAQ differentially affect inflammation and HLA expression, and thereby progression of the disease. We analyzed data of 59 primarily enucleated UM eyes. The type of GNAQ/11 mutation was analyzed using dPCR; chromosome aberrations were determined by Fluorescence in Situ Hybridization (FISH), karyotyping, and single nucleotide polymorphism (SNP) analysis, and mRNA expression by Illumina PCR. Comparing tumors with a GNAQ mutation with those with a GNA11 mutation yielded no significant differences in histopathological characteristics, infiltrate, or HLA expression. When comparing the Q209L mutations with Q209P mutations in tumors with monosomy of chromosome 3, a higher mitotic count was found in the Q209P/M3 tumors (p = 0.007). The Kaplan-Meier (KM) curves between the patients of the different groups were not significantly different. We conclude that the type (Q209P/Q209L) or location of the mutation (GNA11/GNAQ) do not have a significant effect on the immunological characteristics of the tumors, such as infiltrate and HLA Class I expression. Chromosome 3 status was the main determinant in explaining the difference in infiltrate and HLA expression.

The Heterogeneous Distribution of Monosomy 3 in Uveal Melanomas: Implications for Prognostication Based on Fine-Needle Aspiration Biopsies

2007 ◽  
Vol 131 (1) ◽  
pp. 91-96 ◽  
Author(s):  
Willem Maat ◽  
Ekaterina S. Jordanova ◽  
Shama L. van Zelderen-Bhola ◽  
Ed R. Barthen ◽  
Hans W. Wessels ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Fine Needle Aspiration ◽  
Fine Needle Aspiration Biopsy ◽  
Needle Aspiration ◽  
Chromosome 3 ◽  
Fish Analysis ◽  
Paraffin Sections ◽  
Heterogeneous Distribution ◽  
Fine Needle ◽  
Monosomy 3

Abstract Context.—The detection of monosomy 3 in uveal melanomas has repeatedly been associated with adverse outcome. Fine-needle aspiration biopsy is being used to detect monosomy 3 in these tumors, based on the assumption that this chromosomal abnormality is distributed homogeneously throughout the tumor. Objective.—To study the distribution of monosomy 3 in primary uveal melanoma by fluorescence in situ hybridization (FISH). Design.—We studied 50 enucleated eyes with uveal melanoma. In all 50 tumors we performed cytogenetic analysis and FISH using a DNA-specific probe for the centromere region of chromosome 3 on cultured tumor cells. In addition, the percentage of tumor cells with monosomy 3 was assessed by FISH on nuclei, isolated from paraffin-embedded tissue and compared to results of FISH on regular histology sections of the paraffin-embedded tissue. Results.—Combining karyotyping and FISH on cultured cells identified monosomy 3 in 19 (38%) of 50 tumors, whereas FISH on nuclei isolated from paraffin-embedded tissue showed 31 (62%) of 50 as having monosomy for chromosome 3. FISH analysis on paraffin sections showed tumor heterogeneity for copy number of chromosome 3 in at least 7 cases. Conclusions.—FISH analysis on paraffin sections shows that heterogeneity of monosomy of chromosome 3 is a frequent phenomenon in uveal melanoma. FISH on nuclei isolated from paraffin-embedded tissue identifies a higher frequency of monosomy 3 than the traditional combination of karyotyping and FISH on cultured uveal melanoma cells. The practice of assigning patients to risk categories based on fine-needle aspiration biopsy samples from primary uveal melanoma may be subject to error based on the heterogeneous distribution of monosomy 3 in these tumors.

scholarly journals A comprehensive review and performance evaluation of bioinformatics tools for HLA class I peptide-binding prediction

2020 ◽  
Vol 21 (4) ◽  
pp. 1119-1135 ◽  
Author(s):  
Shutao Mei ◽  
Fuyi Li ◽  
André Leier ◽  
Tatiana T Marquez-Lago ◽  
Kailin Giam ◽  
...  
Keyword(s):  
Machine Learning ◽  
T Cell ◽  
Peptide Binding ◽  
Hla Class I ◽  
Machine Learning Algorithms ◽  
Class I ◽  
Target Cells ◽  
Binding Prediction ◽  
Validation Data ◽  
Data Set

Abstract Human leukocyte antigen class I (HLA-I) molecules are encoded by major histocompatibility complex (MHC) class I loci in humans. The binding and interaction between HLA-I molecules and intracellular peptides derived from a variety of proteolytic mechanisms play a crucial role in subsequent T-cell recognition of target cells and the specificity of the immune response. In this context, tools that predict the likelihood for a peptide to bind to specific HLA class I allotypes are important for selecting the most promising antigenic targets for immunotherapy. In this article, we comprehensively review a variety of currently available tools for predicting the binding of peptides to a selection of HLA-I allomorphs. Specifically, we compare their calculation methods for the prediction score, employed algorithms, evaluation strategies and software functionalities. In addition, we have evaluated the prediction performance of the reviewed tools based on an independent validation data set, containing 21 101 experimentally verified ligands across 19 HLA-I allotypes. The benchmarking results show that MixMHCpred 2.0.1 achieves the best performance for predicting peptides binding to most of the HLA-I allomorphs studied, while NetMHCpan 4.0 and NetMHCcons 1.1 outperform the other machine learning-based and consensus-based tools, respectively. Importantly, it should be noted that a peptide predicted with a higher binding score for a specific HLA allotype does not necessarily imply it will be immunogenic. That said, peptide-binding predictors are still very useful in that they can help to significantly reduce the large number of epitope candidates that need to be experimentally verified. Several other factors, including susceptibility to proteasome cleavage, peptide transport into the endoplasmic reticulum and T-cell receptor repertoire, also contribute to the immunogenicity of peptide antigens, and some of them can be considered by some predictors. Therefore, integrating features derived from these additional factors together with HLA-binding properties by using machine-learning algorithms may increase the prediction accuracy of immunogenic peptides. As such, we anticipate that this review and benchmarking survey will assist researchers in selecting appropriate prediction tools that best suit their purposes and provide useful guidelines for the development of improved antigen predictors in the future.

Effect of Heterogeneous Distribution of Monosomy 3 on Prognosis in Uveal Melanoma

2011 ◽  
Vol 135 (8) ◽  
pp. 1042-1047 ◽  
Author(s):  
Inge HG Bronkhorst ◽  
Willem Maat ◽  
Ekaterina S Jordanova ◽  
Wilma GM Kroes ◽  
Nicoline E Schalij-Delfos ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Survival Data ◽  
Cultured Cells ◽  
Cox Proportional Hazards ◽  
Chromosome 3 ◽  
Likelihood Ratios ◽  
Heterogeneous Distribution ◽  
Isolated Nuclei ◽  
Monosomy 3 ◽  
Significant Difference

Context.—Fluorescence in situ hybridization (FISH) analyses on tumor sections and on isolated nuclei showed that even low numbers of cells with monosomy of chromosome 3 adversely affected survival. Objective.—To determine what percentage of uveal melanoma cells with monosomy of chromosome 3 influences patient mortality. Design.—To determine the presence of monosomy 3, karyotyping and FISH on cultured cells and FISH on isolated nuclei were performed on 50 primary uveal melanomas. Clinical and pathologic prognostic factors were assessed and compared with 5-year survival data. Analyses were performed using Cox proportional hazards test, log-rank analysis, sensitivity, specificity, and positive and negative likelihood ratios. Results.—Combined karyotyping and FISH on cultured cells showed monosomy 3 in 19 of 50 cases (38%), whereas determination of the monosomy 3 status by FISH on isolated nuclei with a threshold of 5% assigned 31 of 50 cases (62%) to the monosomy-3 category. When monosomy 3 on isolated nuclei with a cutoff value of 5% was used, a significant difference in 5-year survival was present (hazard ratio, 15.5; P  =  .007), indicating that monosomy 3 in greater than 5% of tumor cells is related to death due to metastases. Conclusion.—In uveal melanoma, the presence of greater than 5% of cells with monosomy 3, as determined by FISH on isolated nuclei, is associated with the development of metastases within 5 years after enucleation.

HLA class-I-restricted and tumor-specific CTL in tumor-infiltrating lymphocytes of patients with gastric cancer

1997 ◽  
Vol 70 (6) ◽  
pp. 631-638 ◽  
Author(s):  
Tomoaki Hoshino ◽  
Naoko Seki ◽  
Megumi Kikuchi ◽  
Terukazu Kuramoto ◽  
Osamu Iwamoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Infiltrating Lymphocytes ◽  
Hla Class I ◽  
Class I ◽  
Infiltrating Lymphocytes

scholarly journals HDAC Inhibition Increases HLA Class I Expression in Uveal Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3690
Author(s):  
Zahra Souri ◽  
Aart G. Jochemsen ◽  
Mieke Versluis ◽  
Annemijn P.A. Wierenga ◽  
Fariba Nemati ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cell Lines ◽  
Uveal Melanoma ◽  
Hdac Inhibitor ◽  
Mrna Level ◽  
Hla Class I ◽  
Class I ◽  
In Vitro Tests ◽  
Hla Class I Antigens

The treatment of uveal melanoma (UM) metastases or adjuvant treatment may imply immunological approaches or chemotherapy. It is to date unknown how epigenetic modifiers affect the expression of immunologically relevant targets, such as the HLA Class I antigens, in UM. We investigated the expression of HDACs and the histone methyl transferase EZH2 in a set of 64 UMs, using an Illumina HT12V4 array, and determined whether a histone deacetylase (HDAC) inhibitor and EZH2 inhibitor modified the expression of HLA Class I on three UM cell lines. Several HDACs (HDAC1, HDAC3, HDAC4, and HDAC8) showed an increased expression in high-risk UM, and were correlated with an increased HLA expression. HDAC11 had the opposite expression pattern. While in vitro tests showed that Tazemetostat did not influence cell growth, Quisinostat decreased cell survival. In the three tested cell lines, Quisinostat increased HLA Class I expression at the protein and mRNA level, while Tazemetostat did not have an effect on the cell surface HLA Class I levels. Combination therapy mostly followed the Quisinostat results. Our findings indicate that epigenetic drugs (in this case an HDAC inhibitor) may influence the expression of immunologically relevant cell surface molecules in UM, demonstrating that these drugs potentially influence immunotherapy.

Different Subsets of Tumor-Infiltrating Lymphocytes Correlate with Macrophage Influx and Monosomy 3 in Uveal Melanoma

2012 ◽  
Vol 53 (9) ◽  
pp. 5370 ◽  
Author(s):  
Inge H. G. Bronkhorst ◽  
T. H. Khanh Vu ◽  
Ekaterina S. Jordanova ◽  
Gregorius P. M. Luyten ◽  
Sjoerd H. van der Burg ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Tumor Infiltrating Lymphocytes ◽  
Monosomy 3 ◽  
Infiltrating Lymphocytes
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