scholarly journals BIOM-16. IMMUNOMIC ANALYSIS OF GLIOBLASTOMA (GBM) USING GENE EXPRESSION PROFILING

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii5-ii5
Author(s):  
Michael Castro ◽  
Nilofar Badra-Azar ◽  
Thomas Kessler ◽  
Moritz Schütte ◽  
Bodo Lange ◽  
...  
Keyword(s):  
Gene Expression ◽  
Antigen Presentation ◽  
Hierarchical Clustering ◽  
Immune Evasion ◽  
Human Cancer ◽  
Progression Free Survival ◽  
Immune Checkpoints ◽  
Successful Implementation ◽  
Cell Trafficking ◽  
Box Plots

Abstract BACKGROUND Despite the success of immunotherapy across the spectrum of human cancer, a successful strategy has not emerged for GBM. While PD-L1 IHC and TMB have demonstrated some utility as predictors of immunotherapy benefit, responsiveness is complexly determined by factors affecting T cell trafficking, antigen presentation, other immune checkpoints, and mediators of immune exhaustion. Thus, we set out to to characterize mediators of immune resistance and their diversity in a population of GBM patients utilizing quantitative gene expression. METHODS A set of 54 immunotherapy and checkpoint relevant genes and seven genes related to immune failure were selected from the literature. RNA gene counts for TCGA glioblastoma multiforme samples (N=163) were downloaded from https://portal.gdc.cancer.gov/. Annotation on subtypes and PFS values were obtained from PMID: 24120142. Gene expression normalization as FPKM, hierarchical clustering and box-plots were performed using R-3.6.0. Statistical differences of gene expression between subtypes were quantified using a TurkeyHSD test. RESULTS A heatmap with hierarchical clustering for immune related genes for the TCGA GBM cohort was generated including colored annotation for the subtype and progression free survival. The graph shows a rough separation into two groups, where one group of the genes is tentatively associated with mesenchymal subtype and shorter survival and showing higher expression for most immune evasion genes. However, a heterogeneity of immune evasion signatures was identified within and across subtypes. Transcripts related to antigen presentation, EZH2, and LDHA varied significantly between GBM subtypes (p < 0.05). CONCLUSION Gene expression analysis has utility to identify specific mediators of immune evasion and to inform the selection of combination therapies for discrete subsets of patients. A Bayesian approach to patient selection for specific immunotherapy strategies may enhance the likelihood of successful implementation of immunotherapy in the clinic.

scholarly journals Leveraging epigenetics to enhance the efficacy of immunotherapy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jonathan D. Licht ◽  
Richard L. Bennett
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Antigen Presentation ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Regulatory Elements ◽  
Chromatin Accessibility ◽  
Epigenetic Modifications ◽  
Main Body ◽  
Epigenetic Mechanisms

Abstract Background Epigenetic mechanisms regulate chromatin accessibility patterns that govern interaction of transcription machinery with genes and their cis-regulatory elements. Mutations that affect epigenetic mechanisms are common in cancer. Because epigenetic modifications are reversible many anticancer strategies targeting these mechanisms are currently under development and in clinical trials. Main body Here we review evidence suggesting that epigenetic therapeutics can deactivate immunosuppressive gene expression or reprogram tumor cells to activate antigen presentation mechanisms. In addition, the dysregulation of epigenetic mechanisms commonly observed in cancer may alter the immunogenicity of tumor cells and effectiveness of immunotherapies. Conclusions Therapeutics targeting epigenetic mechanisms may be helpful to counter immune evasion and improve the effectiveness of immunotherapies.

scholarly journals An Integrative Analysis of microRNA and mRNA Expression–-A Case Study

2008 ◽  
Vol 6 ◽  
pp. CIN.S633 ◽  
Author(s):  
Li-Xuan Qin
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Hierarchical Clustering ◽  
Human Cancer ◽  
Microrna Expression ◽  
Tissue Type ◽  
Integrated Analysis ◽  
Tumor Type ◽  
Cancer Data

Background MicroRNAs are believed to play an important role in gene expression regulation. They have been shown to be involved in cell cycle regulation and cancer. MicroRNA expression profiling became available owing to recent technology advancement. In some studies, both microRNA expression and mRNA expression are measured, which allows an integrated analysis of microRNA and mRNA expression. Results We demonstrated three aspects of an integrated analysis of microRNA and mRNA expression, through a case study of human cancer data. We showed that (1) microRNA expression efficiently sorts tumors from normal tissues regardless of tumor type, while gene expression does not; (2) many microRNAs are down-regulated in tumors and these microRNAs can be clustered in two ways: microRNAs similarly affected by cancer and microRNAs similarly interacting with genes; (3) taking let-7f as an example, targets genes can be identified and they can be clustered based on their relationship with let-7f expression. Discussion Our findings in this paper were made using novel applications of existing statistical methods: hierarchical clustering was applied with a new distance measure–the co-clustering frequency–to identify sample clusters that are stable; microRNA-gene correlation profiles were subject to hierarchical clustering to identify microRNAs that similarly interact with genes and hence are likely functionally related; the clustering of regression models method was applied to identify microRNAs similarly related to cancer while adjusting for tissue type and genes similarly related to microRNA while adjusting for disease status. These analytic methods are applicable to interrogate multiple types of -omics data in general.

scholarly journals Comprehensive Analysis of the Expression, Prognostic Value and Immune Microenvironment of CMTM Family Members in Ovarian Cancer

2021 ◽  
Author(s):  
Mengjun Zhang ◽  
Yue Yin ◽  
Zhenxing Sun ◽  
Yuan Liu ◽  
Yiru Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Prognostic Value ◽  
Immune Cell ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
High Expression ◽  
Immune Checkpoints ◽  
Immune Microenvironment ◽  
Protein Levels

Abstract Background: Ovarian cancer (OV) is one of the most common gynecological malignancies worldwide, and its immunotherapy has considerable prospects. Multiple members of the CMTM family were aberrantly expressed in human cancers and controled key malignant biological processes and immune regulation in cancer development. However, little is known about the function of this gene family in ovarian cancer, especially in terms of immunity.Methods: GEPIA, Oncomine, HPA, Kaplan-Meier plotter, cBioPortal, GeneMANIA and TIMER were used to analyze the differential gene expression, prognostic value, genetic alterations and alterations in the immune microenvironment of the CMTM family in patients with ovarian cancer. Importantly, RT-qPCR was used to verify the gene expression of the CMTM family.Results: CMTM1/3/4/6/7/8 showed abnormally high expression at the mRNA and protein levels in OV tissues based on the GEPIA and HPA databases. RT-qPCR showed that CMTM1/6/8 was highly expressed in ovarian cancer cell lines. Survival analysis showed that high expression of CMTM1/2/3/5/8 can lead to a significant reduction in overall survival and progression-free survival. There were many types of genetic alterations in the CMTM family. And CMTM1/2/3/6 had a certain correlation with the changes of immune microenvironment such as immune cell infiltration and immune checkpoint expression, which may be the potential mechanism of the CMTM family in ovarian cancer.Conclusion: This study confirmed that the CMTM family has abnormal expression in ovarian cancer and can be used as a biomarker for prognostic evaluation. And the CMTM family may be used as a potential target for immunotherapy based on the suppression of immune checkpoints.

scholarly journals Comprehensive Analysis of the Expression, Prognostic Value and Immune Microenvironment of Family Members in Ovarian Cancer

2021 ◽  
Author(s):  
Mengjun Zhang ◽  
Yue Yin ◽  
Zhenxing Sun ◽  
Yuan Liu ◽  
Yiru Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Prognostic Value ◽  
Immune Cell ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
High Expression ◽  
Immune Checkpoints ◽  
Immune Microenvironment ◽  
Protein Levels

Abstract Background: Ovarian cancer (OV) is one of the most common gynecological malignancies worldwide, and its immunotherapy has considerable prospects. Multiple members of the CMTM family were aberrantly expressed in human cancers and controled key malignant biological processes and immune regulation in cancer development. However, little is known about the function of this gene family in ovarian cancer, especially in terms of immunity.Methods: GEPIA, Oncomine, HPA, Kaplan-Meier plotter, cBioPortal, GeneMANIA and TIMER were used to analyze the differential gene expression, prognostic value, genetic alterations and alterations in the immune microenvironment of the CMTM family in patients with ovarian cancer. Importantly, RT-qPCR was used to verify the gene expression of the CMTM family.Results: CMTM1/3/4/6/7/8 showed abnormally high expression at the mRNA and protein levels in OV tissues based on the GEPIA and HPA databases. RT-qPCR showed that CMTM1/6/8 was highly expressed in ovarian cancer cell lines. Survival analysis showed that high expression of CMTM1/2/3/5/8 can lead to a significant reduction in overall survival and progression-free survival. There were many types of genetic alterations in the CMTM family. And CMTM1/2/3/6 had a certain correlation with the changes of immune microenvironment such as immune cell infiltration and immune checkpoint expression, which may be the potential mechanism of the CMTM family in ovarian cancer.Conclusion: This study confirmed that the CMTM family has abnormal expression in ovarian cancer and can be used as a biomarker for prognostic evaluation. And the CMTM family may be used as a potential target for immunotherapy based on the suppression of immune checkpoints.

scholarly journals Gene Expression Analysis of the Bone Marrow Microenvironment Reveals Distinct Immunotypes in Smoldering Multiple Myeloma Associated to Progression to Symptomatic Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Ignacio Isola ◽  
Fara Brasó-Maristany ◽  
David F. Moreno ◽  
Mari-Pau Mena ◽  
Aina Oliver-Calders ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Progression Free Survival ◽  
Immune Checkpoints ◽  
Clinical Parameters ◽  
Free Survival ◽  
Cytotoxic Cells ◽  
Risk Of Progression ◽  
Cytotoxic Molecules

BackgroundWe previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression.MethodsGene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology.ResultsBM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival.ConclusionsOur results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression.

New Trends in Anti-Cancer Therapy: Combining Conventional Chemotherapeutics with Novel Immunomodulators

2018 ◽  
Vol 25 (36) ◽  
pp. 4758-4784 ◽  
Author(s):  
Amy L. Wilson ◽  
Magdalena Plebanski ◽  
Andrew N. Stephens
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
Immune System ◽  
Cancer Therapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Tumour Microenvironment ◽  
Immune Checkpoints ◽  
Tumour Regression ◽  
Cell Trafficking

Cancer is one of the leading causes of death worldwide, and current research has focused on the discovery of novel approaches to effectively treat this disease. Recently, a considerable number of clinical trials have demonstrated the success of immunomodulatory therapies for the treatment of cancer. Monoclonal antibodies can target components of the immune system to either i) agonise co-stimulatory molecules, such as CD137, OX40 and CD40; or ii) inhibit immune checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death-1 (PD-1) and its corresponding ligand PD-L1. Although tumour regression is the outcome for some patients following immunotherapy, many patients still do not respond. Furthermore, chemotherapy has been the standard of care for most cancers, but the immunomodulatory capacity of these drugs has only recently been uncovered. The ability of chemotherapy to modulate the immune system through a variety of mechanisms, including immunogenic cell death (ICD), increased antigen presentation and depletion of regulatory immune cells, highlights the potential for synergism between conventional chemotherapy and novel immunotherapy. In addition, recent pre-clinical trials indicate dipeptidyl peptidase (DPP) enzyme inhibition, an enzyme that can regulate immune cell trafficking to the tumour microenvironment, as a novel cancer therapy. The present review focuses on the current immunological approaches for the treatment of cancer, and summarizes clinical trials in the field of immunotherapy as a single treatment and in combination with chemotherapy.

scholarly journals Alterations in regulatory T cells and immune checkpoint molecules in pancreatic cancer patients receiving FOLFIRINOX or gemcitabine plus nab-paclitaxel

2021 ◽  
Author(s):  
L. Sams ◽  
S. Kruger ◽  
V. Heinemann ◽  
D. Bararia ◽  
S. Haebe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Progression Free Survival ◽  
Ductal Adenocarcinoma ◽  
Immune Checkpoints ◽  
Prognostic Information ◽  
Peripheral Blood Mononuclear

Abstract Purpose This pilot study aimed on generating insight on alterations in circulating immune cells during the use of FOLFIRINOX and gemcitabine/nab-paclitaxel in pancreatic ductal adenocarcinoma (PDAC). Patients and methods Peripheral blood mononuclear cells were isolated before and 30 days after initiation of chemotherapy from 20 patients with advanced PDAC. Regulatory T cells (FoxP3+) and immune checkpoints (PD-1 and TIM-3) were analyzed by flow cytometry and immunological changes were correlated with clinical outcome. Results Heterogeneous changes during chemotherapy were observed in circulating T-cell subpopulations with a pronounced effect on PD-1+ CD4+/CD8+ T cells. An increase in FoxP3+ or PD-1+ T cells had no significant effect on survival. An increase in TIM3+/CD8+ (but not TIM3+/CD4+) T cells was associated with a significant inferior outcome: median progression-free survival in the subgroup with an increase of TIM-3+/CD8+ T cells was 6.0 compared to 14.0 months in patients with a decrease/no change (p = 0.026); corresponding median overall survival was 13.0 and 20.0 months (p = 0.011), respectively. Conclusions Chemotherapy with FOLFIRNOX or gemcitabine/nab-paclitaxel induces variable changes in circulating T-cell populations that may provide prognostic information in PDAC.

scholarly journals A novel gene signature based on five immune checkpoint genes predicts the survival of glioma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wei Zhang ◽  
You Zhai ◽  
Guanzhang Li ◽  
Tao Jiang
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Immune Response ◽  
Nervous System ◽  
Cox Regression ◽  
Gene Signature ◽  
Immune Checkpoints ◽  
The Novel ◽  
The Central Nervous System ◽  
Checkpoint Genes

Abstract Background Glioma is the most common and fatal type of nerve neoplasm in the central nervous system. Several biomarkers have been considered for prognosis prediction, which is not accurate enough. We aimed to carry out a gene signature related to the expression of immune checkpoints which was enough for its performance in prediction. Methods Gene expression of immune checkpoints in TGGA database was filtrated. The 5 selected genes underwent verification by COX and Lasso-COX regression. Next, the selected genes were included to build a novel signature for further analysis. Results Patients were sub-grouped into high and low risk according to the novel signature. Immune response, clinicopathologic characters, and survival showed significant differences between those 2 groups. Terms including “naive,” “effector,” and “IL-4” were screened out by GSEA. The results showed strong relevance between the signature and immune response. Conclusions We constructed a gene signature with 5 immune checkpoints. The signature predicted survival effectively. The novel signature performed more functional than previous biomarkers.

Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion

2021 ◽  
Vol 21 (5) ◽  
pp. 298-312
Author(s):  
Suchit Jhunjhunwala ◽  
Christian Hammer ◽  
Lélia Delamarre
Keyword(s):  
Antigen Presentation ◽  
Immune Evasion
Sign in / Sign up

Export Citation Format

Share Document