scholarly journals Integrating m6A Regulators-Mediated Methylation Modification Models and Tumor Immune Microenvironment Characterization in Caucasian and Chinese Low-Grade Gliomas

2021 ◽  
Vol 9 ◽  
Author(s):  
Wangrui Liu ◽  
Chuanyu Li ◽  
Yuhao Wu ◽  
Wenhao Xu ◽  
Shuxian Chen ◽  
...  
Keyword(s):  
Immune Cells ◽  
Large Scale ◽  
Epigenetic Modification ◽  
Tumor Development ◽  
Strategy Development ◽  
Low Grade ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Genome Heterogeneity

Background: As an important epigenetic modification, m6A methylation plays an essential role in post-transcriptional regulation and tumor development. It is urgently needed to comprehensively and rigorously explore the prognostic value of m6A regulators and its association with tumor microenvironment (TME) infiltration characterization of low-grade glioma (LGG).Methods: Based on the expression of 20 m6A regulatory factors, we comprehensively evaluated the m6A modification patterns of LGG after unsupervised clustering. Subsequent analysis of the differences between these groups was performed to obtain m6A-related genes, then consistent clustering was conducted to generate m6AgeneclusterA and m6AgeneclusterB. A Random Forest and machining learning algorithms were used to reduce dimensionality, identify TME characteristics and predict responses for LGG patients receiving immunotherapies.Results: Evident differential m6A regulators were found in mutation, CNV and TME characteristics of LGG. Based on TCGA and CGGA databases, we identified that m6A regulators clusterA could significantly predict better prognosis (p = 0.00016) which enriched in mTOR signaling pathway, basal transcription factors, accompanied by elevated immune cells infiltration, and decreased IDH and TP53 mutations. We also investigated the distribution of differential genes in m6A regulators clusters which was closely associated with tumor immune microenvironment through three independent cohort comparisons. Next, we established m6Ascore based on previous m6A model, which accurately predicts outcomes in 1089 LGG patients (p < 0.0001) from discovering cohort and 497 LGG patients from testing cohort. Significant TME characteristics, including genome heterogeneity, abidance of immune cells, and clinicopathologic parameters have been found between m6Ascore groups. Importantly, LGG patients with high m6Ascore are confronted with significantly decreased responses to chemotherapies, but benefit more from immunotherapies.Conclusion: In conclusion, this study first demonstrates that m6A modification is crucial participant in tumorigenesis and TME infiltration characterization of LGG based on large-scale cohorts. The m6Ascore provides useful and accurately predict of prognosis and clinical responses to chemotherapy, immunotherapy and therapeutic strategy development for LGG patients.

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...

Can Intratumoral neutrophil lymphocyte ratio (NLR) be a prognostic biomarker in breast cancer patients?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e12573-e12573
Author(s):  
Yoshihisa Tokumaru ◽  
Masanori Oshi ◽  
Vijayashree Murthy ◽  
Eriko Katsuta ◽  
Nobuhisa Matsuhashi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Immune Cells ◽  
Breast Cancer Patients ◽  
Immune Microenvironment ◽  
High Group ◽  
Anti Cancer ◽  
Tumor Immune Microenvironment ◽  
Er Positive

e12573 Background: In breast cancer patients, it is well known that the elevation of neutrophil lymphocyte ratio (NLR) in the blood are reported to associate with poor prognosis based on the notion that neutrophils represent pro-cancer, and lymphocytes represent anti-cancer immune cells. Tumor immune microenvironment has been demonstrated to play critical roles in the outcome of breast cancer patients. However, there is scarce evidence on the clinical relevance of intratumoral NLR in breast cancer patients. In the current study, we hypothesized that intratumoral NLR high tumors are associated with worse survival particularly in TNBC that is known to have high immune cell infiltration. Methods: A total of 1904 breast cancer patients’ data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) and analyzed. NLR was calculated by the gene expressions of CD66b (CEACAM8) and CD8 (CD8A). NLR high and low were divided by the median. Overall Survival (OS) and Disease-Free Survival were calculated utilizing Kaplan Meier method between intratumoral NLR high and low groups. xCell algorithm was used to analyze the infiltrated immune cells within the tumor immune microenvironment as we have previously published. Results: Intratumoral NLR high group was associated with worse OS in whole, ER-positive/HER2-negative, and triple negative (TN) subtypes, in agreement with the previous studies. TN subtype alone demonstrated worse DFS of NLR high group. Surprisingly, gene set enrichment analysis (GSEA) demonstrated no gene set enrichment to NLR high group, which implicates that there is no distinctive mechanism that associate with worse survival. Whereas, immune response-related gene sets significantly enriched to NLR low group in TN subtype. This enrichment was consistent in ER-positive/HER2-negative. Compared with ER-positive/HER2-negative subtype, anti-cancer immune cells such as CD4+ T cells, CD8+ T cells, M1 macrophage, and helper T helper type 1 cells were significantly infiltrated in TN patients (p < 0.001 for all genes), where M2 macrophages and neutrophils were less and regulatory T cells and T helper type 2 cells were more infiltrated in TN subtype. Furthermore, intratumoral NLR was significantly lower in TN compared with ER-positive/HER2-negative subtype (p < 0.001). These results suggest that intratumoral NLR low group is associated with better survival due to favorable tumor immune microenvironment in TN subtype rather than NLR high group has worse survival. Conclusions: Intratumoral NLR low tumor demonstrated more favorable OS and more favorable DFS in TN patients. Intratumoral NLR low breast cancer was associated with enhanced immune response and higher infiltration of anti-cancer immune cells were observed in TN subtype compared to ER-positive/HER2-negative which may contribute to the favorable outcome of in TN breast cancer.

scholarly journals P02.03 Automated cell type specific PD-L1 quantification by artificial intelligence using high throughput bleach & stain 15-marker multiplex fluorescence immunohistochemistry in human cancers

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A8.2-A9
Author(s):  
NC Blessin ◽  
E Bady ◽  
T Mandelkow ◽  
C Yang ◽  
J Raedler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
T Cell Subsets ◽  
Immune Microenvironment ◽  
L1 Data ◽  
Tumor Immune Microenvironment ◽  
Immune Phenotypes ◽  
Fluorescence Immunohistochemistry ◽  
Tumor Entities

BackgroundThe quantification of PD-L1 (programmed cell death ligand 1) has been used to predict patient’s survival, to characterize the tumor immune microenvironment, and to predict response to immune checkpoint therapies. However, a framework to assess the PD-L1 status with a high interobserver reproducibility on tumor cells and different types of immune cells has yet to be established.Materials and MethodsTo study the impact of PD-L1 expression on the tumor immune microenvironment and patient outcome, a framework for fully automated PD-L1 quantification on tumor cells and immune cells was established and validated. Automated PD-L1 quantification was facilitated by incorporating three different deep learning steps for the analysis of more than 80 different neoplasms from more than 10’000 tumor specimens using a bleach & stain 15-marker multiplex fluorescence immunohistochemistry panel (i.e., PD-L1, PD-1, CTLA-4, panCK, CD68, CD163, CD11c, iNOS, CD3, CD8, CD4, FOXP3, CD20, Ki67, CD31). Clinicopathological parameter were available for more than 30 tumor entities and overall survival data were available for 1517 breast cancer specimens.ResultsComparing the automated deep-learning based PD-L1 quantification with conventional brightfield PD-L1 data revealed a high concordance in tumor cells (p<0.0001) as well as immune cells (p<0.0001) and an accuracy of the automated PD-L1 quantification ranging from 90% to 95.2%. Across all tumor entities, the PD-L1 expression level was significantly higher in distinct macrophage/dendritic cell (DC) subsets (identified by CD68, CD163, CD11c, iNOS; p<000.1) and in macrophages/DCs located in the Stroma (p<0.0001) as compared to intratumoral macrophages/DC subsets. Across all different tumor entities, the PD-L1 expression was highly variable and distinct PD-L1 driven immune phenotypes were identified based on the PD-L1 intensity on both tumor and immune cells, the distance between non-exhausted T-cell subsets (i.e. PD-1 and CTLA-4 expression on CD3+CD8+ cytotoxic T-cells, CD3+CD4+ T-helper cells, CD3+CD4+FOXP3+ regulatory T-cells) and tumor cells as well as macrophage/(DC) subtypes. In breast cancer, the PD-L1 fluorescence intensity on tumor cells showed a significantly higher predictive performance for overall survival with an area under receiver operating curves (AUC) of 0.72 (p<0.0001) than the percentage of PD-L1+ tumor cells (AUC: 0.54). In PD-L1 positive as well as negative breast cancers a close spatial relationship between T- cell subsets (CD3+CD4±CD8±FOXP3±PD-1±CTLA-4±) and Macrophage/DC subsets (CD68±CD163±CD11c±iNOS) was found prognostic relevant (p<0.0001).ConclusionsIn conclusion, multiplex immunofluorescence PD-L1 assessment provides cutoff-free/continuous PD-L1 data which are superior to the conventional percentage of PD-L1+ tumor cells and of high prognostic relevance. The combined analysis of spatial PD-L1/PD-1 data and more than 20 different immune cell subtypes of the immune tumor microenvironment revealed distinct PD-L1 immune phenotypes.Disclosure InformationN.C. Blessin: None. E. Bady: None. T. Mandelkow: None. C. Yang: None. J. Raedler: None. R. Simon: None. C. Fraune: None. M. Lennartz: None. S. Minner: None. E. Burandt: None. D. Höflmayer: None. G. Sauter: None. S.A. Weidemann: None.

scholarly journals Characterization of Oral Squamous Cell Carcinoma Associated Inflammation: A Pilot Study

2021 ◽  
Vol 2 ◽  
Author(s):  
Catherine Laliberté ◽  
Nicole Ng ◽  
Denise Eymael ◽  
Kevin Higgins ◽  
Aiman Ali ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Oral Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Immune Cells ◽  
Tumor Development ◽  
Tissue Analysis ◽  
Fluorescent Immunohistochemistry ◽  
Pro Inflammatory Cytokines

Background: Oral squamous cell carcinoma (OSCC) is a devastating disease that is usually associated with a dense associated inflammatory infiltrate. Characterizing tumor-associated inflammation is critical to understand the pathogenies of tumor development and progression.Methods: We have tested a protocol to analyze tissue and salivary immune cells and mediators of 37 patients with OSCC at different stages and compared to eight chronic periodontitis patients and 24 healthy controls. Tissue analysis was based on fluorescent immunohistochemistry (FIHC) and inflammatory mediators were analyzed using a Luminex-based 30-Plex panel. Immune cells were analyzed using multichannel flow cytometry including CD45, CD66b, CD3, CD4, CD8, CD25, CD56, CD68, CD138, PD-1, and PD-L1.Results: We show an increase in OSCC-associated inflammation characterized by increased pro-inflammatory cytokines including IL-6, IL-8, TNFα, and GMCSF and increased salivary immune cells.Conclusion: We described a new method to analyze salivary inflammatory markers that can be used in future studies to monitor disease progression and prognosis.

Clinical relevance of miR-143 expression in ER-positive breast cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e12574-e12574
Author(s):  
Yoshihisa Tokumaru ◽  
Masanori Oshi ◽  
Eriko Katsuta ◽  
Nobuhisa Matsuhashi ◽  
Manabu Futamura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Immune Cells ◽  
High Expression ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Immune Microenvironment ◽  
Anti Cancer ◽  
Tumor Immune Microenvironment ◽  
Er Positive

e12574 Background: MicroRNA-143(miR-143) is a well-known tumor suppressive microRNA in various malignancies, including breast cancer. Recently, the tumor immune microenvironment has been reported to associate with progression of breast cancers. However, the association with the tumor immune microenvironment and miR-143 in breast cancers remains ambiguous. Given these backgrounds, we hypothesized that high expression of miR-143 is associated with favorable effect to the tumor immune microenvironment which leads to better survival of ER positive breast cancer patients. Methods: Two major publicly available breast cancer cohorts were used for this study. A total of 753 patients from The Cancer Genome Atlas (TCGA) and total of 1283 patients from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used. Results: We defined the higher quartile of miR-143 expression levels as high and the remainder as low expression groups. There was no significant difference in patient clinicopathlogical features between two groups. Gene set enrichment analysis (GSEA) revealed that miR-143 high expression tumors enriched Helper T cell type 1 (Th1) related gene sets indicating the upregulation of anti-cancer immune cells. Also, the cell composition of anti-cancer immune cells, such as Th1 and Macrophage M1 were higher with miR-143 high tumors (p < 0.001 and p < 0.01 respectively) in whole group. On the contrary, pro-cancer immune cells such as Th2 and M1 were lower with miR-143 high tumors (p < 0.01 and p < 0.001 respectively) in whole group. Interestingly, among the subtypes, we found that ER positive subgroup followed this trend of high infiltration rate of anti-cancer immune cells and low infiltration rate of pro-cancer immune cells. Furthermore, only ER positive subgroup demonstrated the survival benefit with miR-143 high expression tumors. Conclusions: We demonstrated that high expression of miR-143 in ER breast cancer associate with favorable tumor immune microenvironment, upregulation of the anti-cancer immune cells and suppression of the pro-cancer immune cells, and associate with better survival of the breast cancer patients.

scholarly journals Tumor Immune Microenvironment and Its Related miRNAs in Tumor Progression

2021 ◽  
Vol 12 ◽  
Author(s):  
Yingying Xing ◽  
Guojing Ruan ◽  
Haiwei Ni ◽  
Hai Qin ◽  
Simiao Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Immune Cells ◽  
Suppressor Cells ◽  
Immune Microenvironment ◽  
Non Coding Rna ◽  
Tumor Immune Microenvironment ◽  
Downstream Gene Expression

MiRNA is a type of small non-coding RNA, by regulating downstream gene expression that affects the progression of multiple diseases, especially cancer. MiRNA can participate in the biological processes of tumor, including proliferation, invasion and escape, and exhibit tumor enhancement or inhibition. The tumor immune microenvironment contains numerous immune cells. These cells include lymphocytes with tumor suppressor effects such as CD8+ T cells and natural killer cells, as well as some tumor-promoting cells with immunosuppressive functions, such as regulatory T cells and myeloid-derived suppressor cells. MiRNA can affect the tumor immune microenvironment by regulating the function of immune cells, which in turn modulates the progression of tumor cells. Investigating the role of miRNA in regulating the tumor immune microenvironment will help elucidate the specific mechanisms of interaction between immune cells and tumor cells, and may facilitate the use of miRNA as a predictor of immune disorders in tumor progression. This review summarizes the multifarious roles of miRNA in tumor progression through regulation of the tumor immune microenvironment, and provides guidance for the development of miRNA drugs to treat tumors and for the use of miRNA as an auxiliary means in tumor immunotherapy.

scholarly journals Development and validation of genomic and epigenomic signatures associated with tumor immune microenvironment in hepatoblastoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yanbing Zhang ◽  
Tian Zhang ◽  
Qiang Yin ◽  
Haiyan Luo
Keyword(s):  
Immune Cells ◽  
Hepg2 Cells ◽  
Migration And Invasion ◽  
Immune Microenvironment ◽  
Hub Genes ◽  
Normal Tissues ◽  
Tumor Immune Microenvironment ◽  
Sample Correlation ◽  
Development And Validation

Abstract Background This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment. Methods Aberrantly methylated and expressed genes were obtained by comprehensively analyzing gene expression and DNA methylation profiles from GSE81928, GSE75271 and GSE78732 datasets. Their biological functions were predicted by the STRING and Metascape databases. CIBERSORT was utilized for inferring the compositions of tumor-infiltrating immune cells (TIICs) in each sample. Correlation between hub genes and immune cells was then analyzed. Hub genes were validated in hepatoblastoma tissues via western blot or immunohistochemistry. After transfection with sh-NOTUM, migration and invasion of HuH-6 and HepG2 cells were investigated. The nude mouse tumorigenesis model was constructed. Results Totally, 83 aberrantly methylated and expressed genes were determined in hepatoblastoma, which were mainly involved in metabolic and cancer-related pathways. Moreover, their expression was liver-specific. 13 hub genes were screened, which were closely related to immune cells in hepatoblastoma tissues. Among them, it was confirmed that AXIN2, LAMB1 and NOTUM were up-regulated and SERPINC1 was down-regulated in hepatoblastoma than normal tissues. NOTUM knockdown distinctly weakened migration and invasion of HuH-6 and HepG2 cells and tumor growth in vivo. Conclusions This study identified aberrantly methylated and expressed signatures that were in relation to immune microenvironment in hepatoblastoma. Targeting NOTUM hub gene could suppress migration and invasion of hepatoblastoma cells. Thus, these aberrantly methylated and expressed genes might act as therapeutic agents in hepatoblastoma therapy.

scholarly journals Characterization of the m6A-Associated Tumor Immune Microenvironment in Prostate Cancer to Aid Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Zezhen Liu ◽  
Jiehui Zhong ◽  
Jie Zeng ◽  
Xiaolu Duan ◽  
Jianming Lu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Poor Prognosis ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Cell Infiltration ◽  
Intratumor Heterogeneity ◽  
Immune Microenvironment ◽  
Th2 Cell ◽  
Tumor Immune Microenvironment

The aim of this study was to elucidate the correlation between m6A modification and the tumor immune microenvironment (TIME) in prostate cancer (PCa) and to identify the m6A regulation patterns suitable for immune checkpoint inhibitors (ICIs) therapy. We evaluated the m6A regulation patterns of PCa based on 24 m6A regulators and correlated these modification patterns with TIME characteristics. Three distinct m6A regulation patterns were determined in PCa. The m6A regulators cluster with the best prognosis had significantly increased METTL14 and ZC3H13 expression and was characterized by low mutation rate, tumor heterogeneity, and neoantigens. The m6A regulators cluster with a poor prognosis had markedly high KIAA1429 and HNRNPA2B1 expression and was characterized by high intratumor heterogeneity and Th2 cell infiltration, while low Th17 cell infiltration and Macrophages M1/M2. The m6Ascore was constructed to quantify the m6A modification pattern of individual PCa patients based on m6A-associated genes. We found that the low-m6Ascore group with poor prognosis had a higher immunotherapeutic response rate than the high-m6Ascore group. The low-m6Ascore group was more likely to benefit from ICIs therapy. This study was determined that immunotherapy is more effective in low-m6Ascore PCa patients with poor prognosis.

scholarly journals Pseudogene HLA-DRB6 Regulates Immune Microenvironment of Cutaneous Melanoma by miR-338/CXCL10 Axis

2022 ◽  
Author(s):  
Jianmin Ren ◽  
Jinglu Yu ◽  
Yang Shi ◽  
Inam Ullah Khan ◽  
Jiansheng Huang
Keyword(s):  
Single Cell ◽  
Immune Cells ◽  
Cutaneous Melanoma ◽  
Target Genes ◽  
Mrna Levels ◽  
Sequencing Data ◽  
Immune Microenvironment ◽  
Potential Biomarker ◽  
Tumor Immune Microenvironment ◽  
The Relationship

Abstract Background: The relationship between the pseudogene and tumor immune microenvironment in cutaneous melanoma is unclear. In this study, we analyzed the role of the pseudogene HLA-DRB6 and its effect on the tumor immune microenvironment in skin cutaneous melanoma (SKCM) using bioinformatics tools. Method: The GEPIA database was used to analyze the expression of HLA-DRB6 and CXCL10 mRNA in tumor tissues. The TIMER database was used to analyze the relationship between mRNA levels and the infiltration of immune cells. The enrichment of HLA-DRB6 and CXCL10 in melanoma tissues was analyzed by single cell portal. The binding sites of HLA-DRB6 with its target genes was predicted via starBase database. The gene expression profiling and clinical data from GEO database (GSE94873) was used to verify the potential of CXCL10 as a biomarker. Result: The expression of HLA-DRB6 in SKCM tumor is higher than in normal tissues, and patients with high HLA-DRB6 expression had a better prognosis (P<0.05). Furthermore, HLA-DRB6 is positively correlated with the infiltration of immune cells such as B cells, CD4+ T, and CD8+ T lymphocytes, and the expression of immune checkpoint molecules such as PD-1, PD-L1, and CTLA-4. Single cell transcriptome sequencing data showed that HLA-DRB6 is mainly enriched in macrophages and had the highest correlation with CXCL10 than other chemokines (cor=0.66, P<0.0001). In addition, we found that CXCL10 can be used as a potential biomarker for predicting responsiveness and survival rate in SKCM patients who treated with Tremelimumab (a human anti-CTLA-4 antibody). Conclusion: In the microenvironment of SKCM, HLA-DRB6 is mainly enriched in macrophages and regulates the expression of CXCL10 through the ceRNA mechanism. Furthermore, the CXCL10 in peripheral blood can be used as a biomarker to predict the responsiveness and the prognosis for patients treated with tremelimumab.

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