scholarly journals Significance of CD47 and Its Association With Tumor Immune Microenvironment Heterogeneity in Ovarian Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Lan Yu ◽  
Yi Ding ◽  
Ting Wan ◽  
Ting Deng ◽  
He Huang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Prognostic Biomarker ◽  
Gene Set Enrichment Analysis ◽  
Cancer Prognosis ◽  
Expression Level ◽  
Immune Microenvironment ◽  
Immune Infiltration ◽  
Tumor Immune Microenvironment

BackgroundIt was reported that tumor heterogeneity and the surrounding tumor microenvironment (TME) in ovarian cancer affects immunotherapy efficacy and patient outcomes. And the TME of ovarian cancer is intrinsically heterogeneous. CD47 plays vital roles in cell functional behavior and immune homeostasis relating to cancer prognosis. But how it affects TME and its contribution to heterogeneity in ovarian cancer has not been fully illustrated. Therefore, we aimed to identify a prognostic biomarker which may help explain tumor immune microenvironment heterogeneity of ovarian cancer.MethodsCancer single-cell state atlas (CancerSEA) was used to evaluate functional role of CD47. Several bioinformatics database including Oncomine, Gene Expression Profiling Interaction Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), The Human Protein Atlas (HPA), Ualcan and Kaplan-Meier plotter (KM plotter) were applied to illustrate correlation of CD47 with ovarian cancer prognosis and immune infiltration. Tumor Immune Single-cell Hub (TISCH) single cell database was employed to evaluate correlation of CD47 with tumor microenvironment. GeneMANIA was implemented to identify regulation networks of CD47. Differentially expressed genes (DEGs) between CD47 high and low expression groups were analyzed with R package DESeq2. Kyoto encyclopedia of genes and genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were utilized to explore how CD47 affect the immune related cell signaling pathway.ResultsCD47 expression was upregulated and connected to worse OS and PFS in ovarian cancer. Close relation was found between CD47 expression level and immune infiltration in ovarian cancer, especially with Treg cells, Monocytes, Macrophages and T cell exhaustion (P<0.05). The CD47 expression level was relatively low in plasma cells, dendritic cells and Mono/Macro cells of OV_GSE115007, in myofibroblasts, fibroblasts and endothelial cells of OV_GSE118828, compared to malignant cells of OV_GSE118828 dataset. The cell components and distribution in primary and metastatic ovarian cancer are quite distinct, which may lead to TME heterogeneity of ovarian cancer.ConclusionOur results indicated that CD47 is closely correlated to ovarian cancer immune microenvironment and might induce ovarian cancer heterogeneity. Therefore, CD47 may be used as a candidate prognostic biomarker and provide us with new insights into potential immunotherapy in ovarian cancer patients.

scholarly journals Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

2021 ◽  
Author(s):  
Inga-Maria Launonen ◽  
Nuppu Lyytikäinen ◽  
Julia Casado ◽  
Ella Anttila ◽  
Angéla Szabó ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Single Cells ◽  
High Grade ◽  
Prognostic Role ◽  
Immune Microenvironment ◽  
Proteomic Data ◽  
Tumor Immune Microenvironment ◽  
Cellular Phenotypes

Abstract The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generated spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes (HRwt). We identified a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we found an opposing prognostic role of a proliferative tumor-cell phenotypic subpopulation in the HR-genotypes, which associated with enhanced spatial tumor-immune interactions by the CD8+ and CD4+T-cells in BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the premise to improve immunotherapeutic strategies and patient stratification in HGSC.

scholarly journals CLDN6 and CLDN10 are Associated with Immune Infiltration of Ovarian Cancer: A Study of Claudin Family

2020 ◽  
Author(s):  
Peipei Gao ◽  
Ting Peng ◽  
Canhui Cao ◽  
Shitong Lin ◽  
Ping Wu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Markers ◽  
Immune Infiltration ◽  
Kaplan Meier ◽  
The Relationship

Abstract Background: Claudin family is a group of membrane proteins related to tight junction. There are many studies about them in cancer, but few studies pay attention to the relationship between them and the tumor microenvironment. In our research, we mainly focused on the genes related to the prognosis of ovarian cancer, and explored the relationship between them and the tumor microenvironment of ovarian cancer.Methods: The cBioProtal provided the genetic variation pattern of claudin gene family in ovarian cancer. The ONCOMINE database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to exploring the mRNA expression of claudins in cancers. The prognostic potential of these genes was examined via Kaplan-Meier plotter. Immunologic signatures were enriched by gene set enrichment analysis (GSEA). The correlations between claudins and the tumor microenvironment of ovarian cancer were investigated via Tumor Immune Estimation Resource (TIMER).Results: In our research, claudin genes were altered in 363 (62%) of queried patients/samples. Abnormal expression levels of claudins were observed in various cancers. Among them, we found that CLDN3, CLDN4, CLDN6, CLDN10, CLDN15 and CLDN16 were significantly correlated with overall survival of patients with ovarian cancer. GSEA revealed that CLDN6 and CLDN10 were significantly enriched in immunologic signatures about B cell, CD4 T cell and CD8 T cell. What makes more sense is that CLDN6 and CLDN10 were found related to the tumor microenvironment. CLDN6 expression was negatively correlated with immune infiltration level in ovarian cancer, and CLDN10 expression was positively correlated with immune infiltration level in ovarian cancer. Further study revealed the CLDN6 expression level was negatively correlated with gene markers of various immune cells in ovarian cancer. And, the expression of CLDN10 was positive correlated with gene markers of immune cells in ovarian cancer.Conclusions: CLDN6 and CLDN10 were prognostic biomarkers, and correlated with immune infiltration in ovarian cancer. Our results revealed new roles for CLDN6 and CLDN10, and they were potential therapeutic targets in the treatment of ovarian cancer.

scholarly journals NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xu-Sheng Liu ◽  
Lu-Meng Zhou ◽  
Ling-Ling Yuan ◽  
Yan Gao ◽  
Xue-Yan Kui ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Prognostic Biomarker ◽  
Aerobic Glycolysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Expression Level ◽  
Data Sets ◽  
Translational Initiation ◽  
Immune Infiltration ◽  
The Relationship

BackgroundOverexpression of NPM1 can promote the growth and proliferation of various tumor cells. However, there are few studies on the comprehensive analysis of NPM1 in lung adenocarcinoma (LUAD).MethodsTCGA and GEO data sets were used to analyze the expression of NPM1 in LUAD and clinicopathological analysis. The GO/KEGG enrichment analysis of NPM1 co-expression and gene set enrichment analysis (GSEA) were performed using R software package. The relationship between NPM1 expression and LUAD immune infiltration was analyzed using TIMER, GEPIA database and TCGA data sets, and the relationship between NPM1 expression level and LUAD m6A modification and glycolysis was analyzed using TCGA and GEO data sets.ResultsNPM1 was overexpressed in a variety of tumors including LUAD, and the ROC curve showed that NPM1 had a certain accuracy in predicting the outcome of tumors and normal samples. The expression level of NPM1 in LUAD is significantly related to tumor stage and prognosis. The GO/KEGG enrichment analysis indicated that NPM1 was closely related to translational initiation, ribosome, structural constituent of ribosome, ribosome, Parkinson disease, and RNA transport. GSEA showed that the main enrichment pathway of NPM1-related differential genes was mainly related to mTORC1 mediated signaling, p53 hypoxia pathway, signaling by EGFR in cancer, antigen activates B cell receptor BCR leading to generation of second messengers, aerobic glycolysis and methylation pathways. The analysis of TIMER, GEPIA database and TCGA data sets showed that the expression level of NPM1 was negatively correlated with B cells and NK cells. The TCGA and GEO data sets analysis indicated that the NPM1 expression was significantly correlated with one m6A modifier related gene (YTHDF2) and five glycolysis related genes (ENO1, HK2, LDHA, LDHB and SLC2A1).ConclusionNPM1 is a prognostic biomarker involved in immune infiltration of LUAD and associated with m6A modification and glycolysis. NPM1 can be used as an effective target for diagnosis and treatment of LUAD.

scholarly journals Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

2021 ◽  
Author(s):  
Inga-Maria Launonen ◽  
Nuppu Lyytikäinen ◽  
Julia Casado ◽  
Ella Anttila ◽  
Angéla Szabó ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Single Cell ◽  
Spatial Data ◽  
Single Cells ◽  
High Grade ◽  
Spatial Interactions ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Cellular Phenotypes

Abstract The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis on 112 tumor cores we generated single-cell spatial data for 21 markers in 124,623 single cells from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and 13 tumors without any alterations in HR genes (HRwt). We identified a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we found an opposing prognostic role of a proliferative tumor-cell phenotypic subpopulation in the HR-genotypes, which associated with enhanced spatial interactions in the tumor-immune cellular communities. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the premise to improve immunotherapeutic strategies and patient stratification in HGSC.

scholarly journals NRAS Expression is Associated With Prognosis and Tumor Immune Microenvironment in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Yueren Yan ◽  
Zhendong Gao ◽  
Han Han ◽  
Yue Zhao ◽  
Yang Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Adenocarcinoma ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Immune Microenvironment ◽  
Kaplan Meier ◽  
Tumor Immune Microenvironment ◽  
Cox Analysis

Abstract Purpose: NRAS plays a pivotal role in progression of various kinds of somatic malignancies; however, the correlation between NRAS and lung adenocarcinoma is less known. We aim to analyze the prognostic value of NRAS expression in lung adenocarcinoma, and explore the relationship between NRAS and tumor immune microenvironment. Methods: We obtained the transcriptome pofiles and clinical data of LUAD from The Cancer Genome Atlas database and three Genome Expression Omnibus datasets. Specimens from 325 patients with completely resected lung adenocarcinoma were collected for immunohistochemical assays of NRAS, PD-L1, PD-1 and TIM-3. Then we performed gene set enrichment analysis to investigate cancer-related and immune-related signaling pathways. TIMER algorithms were performed to evaluate tumor immune infiltrating cells and immune-related biomarkers.Results: Compared with adjacent non-tumor tissue, NRAS expression was significantly upregulated in LUAD tissue. NRAS expression was significantly correlated with more advanced stage and positive lymph nodes. Kaplan-Meier curves and Cox analysis suggested that high NRAS expression led to a poor prognosis, and could be an independent prognostic factor in LUAD patients. Besides, NRAS expression was positively correlated with CD8+ T cells, macrophages, and neutrophils, and negatively correlated with B cells and CD4+ T cells. The expression level of NRAS was positively correlated with PD-L1, PD-1, and TIM-3 both at RNA and protein level. Conclusions: To conclude, we found NRAS a novel prognostic biomarker in LUAD. Besides, the expression level of NRAS may influence the prognosis of LUAD via various kinds of cancer-related pathways and remodeling TIM.

scholarly journals Abstract 2747: Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer

2021 ◽  
Author(s):  
Inga-Maria P. Launonen ◽  
Nuppu Lyytikäinen ◽  
Julia Casado ◽  
Ella A. Anttila ◽  
Connor A. Jacobson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Single Cell ◽  
Cell Tumor ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment

scholarly journals Association of CLDN6 and CLDN10 With Immune Microenvironment in Ovarian Cancer: A Study of the Claudin Family

2021 ◽  
Vol 12 ◽  
Author(s):  
Peipei Gao ◽  
Ting Peng ◽  
Canhui Cao ◽  
Shitong Lin ◽  
Ping Wu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cell ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Immune Microenvironment ◽  
Gene Markers ◽  
Expression Levels ◽  
Tumor Immune Microenvironment

BackgroundThe claudin family is a group of transmembrane proteins related to tight junctions. While their involvement in cancer has been studied extensively, their relationship with the tumor immune microenvironment remains poorly understood. In this research, we focused on genes related to the prognosis of ovarian cancer and explored their relationship with the tumor immune microenvironment.MethodsThe cBioPortal for Cancer Genomics database was used to obtain the genetic variation pattern of the claudin family in ovarian cancer. The ONCOMINE and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to explore the mRNA expression of claudins in cancers. The prognostic potential of these genes was examined via the Kaplan-Meier plotter. The enrichment of immunological signatures was determined by gene set enrichment analysis (GSEA). The correlations between claudins and the tumor immune microenvironment in ovarian cancer were investigated via the Tumor Immune Estimation Resource (TIMER).ResultsClaudin genes were altered in 363 (62%) of queried patients/samples. Abnormal expression levels of claudins were observed in various cancers. Among them, CLDN3, CLDN4, CLDN6, CLDN10, CLDN15, and CLDN16 were significantly correlated with overall survival in patients with ovarian cancer. GSEA revealed that CLDN6 and CLDN10 were significantly enriched in immunological signatures of B cell, CD4 T cell, and CD8 T cell. Furthermore, CLDN6 and CLDN10 were negatively correlated and positively correlated, respectively, with immune cell infiltration in ovarian cancer. The expression levels of CLDN6 and CLDN10 were also negatively correlated and positively correlated, respectively, with various gene markers of immune cells in ovarian cancer. Thus, CLDN6 and CLDN10 may participate in immune cell infiltration in ovarian cancer, and these mechanisms may be the reason for poor prognosis.ConclusionOur study showed that CLDN6 and CLDN10 were prognostic biomarkers correlated with the immune microenvironment in ovarian cancer. These results reveal new roles for CLDN6 and CLDN10 as potential therapeutic targets in the treatment of ovarian cancer.

scholarly journals Modulation of Immune Infiltration of Ovarian Cancer Tumor Microenvironment by Specific Subpopulations of Fibroblasts

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3184
Author(s):  
Ji Wang ◽  
Frank H. C. Cheng ◽  
Jessica Tedrow ◽  
Wennan Chang ◽  
Chi Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Tumor Microenvironment ◽  
Functional Module ◽  
Treatment Modalities ◽  
Functional Modules ◽  
Immune Microenvironment ◽  
Immune Infiltration ◽  
Immune Response Genes ◽  
Cancer Tumor

Tumor immune infiltration plays a key role in the progression of solid tumors, including ovarian cancer, and immunotherapies are rapidly emerging as effective treatment modalities. However, the role of cancer-associated fibroblasts (CAFs), a predominant stromal constituent, in determining the tumor-immune microenvironment and modulating efficacy of immunotherapies remains poorly understood. We have conducted an extensive bioinformatic analysis of our and other publicly available ovarian cancer datasets (GSE137237, GSE132289 and GSE71340), to determine the correlation of fibroblast subtypes within the tumor microenvironment (TME) with the characteristics of tumor-immune infiltration. We identified (1) four functional modules of CAFs in ovarian cancer that are associated with the TME and metastasis of ovarian cancer, (2) immune-suppressive function of the collagen 1,3,5-expressing CAFs in primary ovarian cancer and omental metastases, and (3) consistent positive correlations between the functional modules of CAFs with anti-immune response genes and negative correlation with pro-immune response genes. Our study identifies a specific fibroblast subtype, fibroblast functional module (FFM)2, in the ovarian cancer tumor microenvironment that can potentially modulate a tumor-promoting immune microenvironment, which may be detrimental toward the effectiveness of ovarian cancer immunotherapies.

scholarly journals Characterizing the Tumor Immune Microenvironment with Tyramide-Based Multiplex Immunofluorescence

2020 ◽  
Vol 25 (4) ◽  
pp. 417-432
Author(s):  
Hidetoshi Mori ◽  
Jennifer Bolen ◽  
Louis Schuetter ◽  
Pierre Massion ◽  
Clifford C. Hoyt ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Multispectral Imaging ◽  
Imaging System ◽  
Predictive Biomarkers ◽  
Cell Types ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Manual Processing ◽  
Cell Densities ◽  
Immune Profiling

AbstractMultiplex immunofluorescence (mIF) allows simultaneous antibody-based detection of multiple markers with a nuclear counterstain on a single tissue section. Recent studies have demonstrated that mIF is becoming an important tool for immune profiling the tumor microenvironment, further advancing our understanding of the interplay between cancer and the immune system, and identifying predictive biomarkers of response to immunotherapy. Expediting mIF discoveries is leading to improved diagnostic panels, whereas it is important that mIF protocols be standardized to facilitate their transition into clinical use. Manual processing of sections for mIF is time consuming and a potential source of variability across numerous samples. To increase reproducibility and throughput we demonstrate the use of an automated slide stainer for mIF incorporating tyramide signal amplification (TSA). We describe two panels aimed at characterizing the tumor immune microenvironment. Panel 1 included CD3, CD20, CD117, FOXP3, Ki67, pancytokeratins (CK), and DAPI, and Panel 2 included CD3, CD8, CD68, PD-1, PD-L1, CK, and DAPI. Primary antibodies were first tested by standard immunohistochemistry and single-plex IF, then multiplex panels were developed and images were obtained using a Vectra 3.0 multispectral imaging system. Various methods for image analysis (identifying cell types, determining cell densities, characterizing cell-cell associations) are outlined. These mIF protocols will be invaluable tools for immune profiling the tumor microenvironment.

scholarly journals The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment

2021 ◽  
Author(s):  
Wyatt M. Becicka ◽  
Peter Bielecki ◽  
Morgan Lorkowski ◽  
Taylor J. Moon ◽  
Yahan Zhang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cells ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Immunosuppressive Tumor Microenvironment

The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. To reprogram the tumor-resident innate immune cells, we developed an...

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