IGLL5 is correlated with tumor‐infiltrating immune cells in clear cell renal cell carcinoma

Abstract Background: Eukaryotic initiation factor 3a, EIF3A, as a “reader” protein for RNA methylation, has been found to be related to promote tumorigenesis in different variety of cancers. The impaction of EIF3A in clear cell renal cell carcinoma (ccRCC) has yet to be expounded. This study aimed to identify the prognostic value of EIF3A in ccRCC and investigate the relationship between expression and immune infiltration.Methods: We collected 29 m6a related mRNA data and clinicopathological parameters from Cancer Genmoe Atlas (TCGA) database. Logistic regression analyses were used to analyze the correlation between EIF3A expression and clinical characteristics. Immunohistochemistry (IHC) were applied to examine EIF3A levels in normal and ccRCC tissues. Univariate and multivariate analyses were conducted to recognize forcefully independent factor in associated with overall survival (OS) and diseases free survival (DFS). Nomogram was aim at predicting the 1-, 3-and 5-year survival probabilities. Gene set enrichment analysis (GSEA) was carried out to the potential function and related signaling pathways of EIF3A expression. To investigate EIF3A of co-expressed genes, we used LinkedOmics and its result was undertaken enrichment analysis. Simultaneously, to employ LinkedOmics and STRING dataset drew a conclusion that EIF3A co-expressed genes and visualized via Cytoscape. Finally, we evaluated that EIF3A expression correlated between with infiltration of immune cells and the expression of marker genes in ccRCC by Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA).Result: EIF3A expression was significantly different between ccRCC tissues and normal tissues. EIF3A expression was connected with poor prognostic clinicopathological factors, and K–M analyses revealed that low EIF3A expression was correlated with poor prognosis. The result of univariate and multivariate analyses proved that EIF3A was a prognostic factor in ccRCC patients. GSEA results indicated that high expression was enriched in renal cell carcinoma pathway and so on. EIF3A expression was significantly positively correlated with B cells, CD8+T cells, CD4+T cells, neutrophils, macrophages, and dendritic cells. Furthermore, EIF3A expression was associated with most of marker genes of immune cells.Conclusions: EIF3A could serve as potential biomarkers for prognostic and diagnostic stratification factor for ccRCC and is related with immune cells infiltrates.

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Prognostic value of infiltrating immune cells in clear cell renal cell carcinoma (ccRCC)

Journal of Cellular Biochemistry ◽

10.1002/jcb.29479 ◽

2019 ◽

Vol 121 (3) ◽

pp. 2571-2581 ◽

Cited By ~ 5

Author(s):

Shiyi Liu ◽

Saijiao Li ◽

Yanqing Wang ◽

Feiyan Wang ◽

Li Zhang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Cells ◽

Renal Cell ◽

Prognostic Value ◽

Clear Cell ◽

Cell Renal Cell Carcinoma

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The pattern and prognostic relevance of immune activity scores and tumor-infiltrating immune cells in metastatic clear cell renal cell carcinoma: Evidence from multiple datasets

International Immunopharmacology ◽

10.1016/j.intimp.2020.106651 ◽

2020 ◽

Vol 85 ◽

pp. 106651

Author(s):

Bowen Shi ◽

Jun Qi

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Cells ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma ◽

Immune Activity ◽

Prognostic Relevance ◽

Multiple Datasets

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Identification and validation of dichotomous immune subtypes based on intratumoral immune cells infiltration in clear cell renal cell carcinoma patients

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000447 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000447

Author(s):

Ying Xiong ◽

Zewei Wang ◽

Quan Zhou ◽

Han Zeng ◽

Hongyu Zhang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Treatment Response ◽

Immune Cells ◽

Renal Cell ◽

Immune Cell ◽

Clear Cell ◽

Biological Pathways ◽

Cell Renal Cell Carcinoma ◽

Free Survival

BackgroundIncreasing evidence has elucidated the clinical significance of tumor infiltrating immune cells in predicting outcomes and therapeutic efficacy. In this study, we comprehensively analyze the tumor microenvironment (TME) immune cell infiltrations in clear cell renal cell carcinoma (ccRCC) and correlated the infiltration patterns with anti-tumor immunity and clinical outcomes.MethodsWe analyzed immune cell infiltrations in four independent cohorts, including the KIRC cohort of 533 patients, the Zhongshan ccRCC cohorts of 259 patients, the Zhongshan fresh tumor sample cohorts of 20 patients and the Zhongshan metastatic ccRCC cohorts of 87 patients. Intrinsic patterns of immune cell infiltrations were evaluated for associations with clinicopathological characteristics, underlying biological pathways, genetic changes, oncological outcomes and treatment responses.ResultsUnsupervised clustering of tumor infiltrating immune cells identified two microenvironment subtypes, TMEcluster-A and TMEcluster-B. Gene markers and biological pathways referring to immune evasion were upregulated in TMEcluster-B. TMEcluster-B associated with poor overall survival (p<0.001; HR 2.629) and recurrence free survival (p=0.012; HR 1.870) in ccRCC validation cohort. TMEcluster-B cases had worse treatment response (p=0.009), overall survival (p<0.001; HR 2.223) and progression free survival (p=0.015; HR 2.7762) in metastatic ccRCC cohort. The predictive accuracy of International Metastatic Database Consortium risk score was improved after incorporation of TME clusters.ConclusionsTMEcluster-A featured increased mast cells infiltration, prolonged survival and better treatment response. TMEcluster-B was a heavily infiltrated but immunosuppressed phenotype enriched for macrophages, CD4+T cells, Tregs, CD8+T cells and B cells. TMEcluster-B predicted dismal survival and worse treatment response in clear cell renal cell carcinoma patients.

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Atezolizumab plus bevacizumab in non-clear cell renal cell carcinoma (NccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (ccRCCsd): Updated results of activity and predictive biomarkers from a phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4583 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4583-4583 ◽

Cited By ~ 7

Author(s):

Ronan Flippot ◽

Bradley Alexander McGregor ◽

Abdallah Flaifel ◽

Kathryn P. Gray ◽

Sabina Signoretti ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Phase Ii ◽

Immune Cells ◽

Renal Cell ◽

Clear Cell ◽

Predictive Biomarkers ◽

Cell Renal Cell Carcinoma ◽

Immune Infiltrate ◽

Sarcomatoid Differentiation

4583 Background: NccRCC and ccRCCsd are aggressive tumors associated with poor prognosis and response to therapy. Combination strategies co-targeting VEGF signaling and inhibitory immune checkpoints are highly active in clear-cell renal cell carcinoma, but data is lacking in NccRCC and ccRCCsd. We conducted a multicenter, open-label, single arm phase II trial of atezolizumab plus bevacizumab in NccRCC and ccRCCsd. Methods: Patients with NccRCC and ccRCCsd ( > 20% sarcomatoid differentiation), and ECOG performance status of 0-2 were eligible. Prior systemic treatment was allowed with the exception of prior PD-1/PD-L1-directed therapy. Atezolizumab 1200mg and bevacizumab 15mg/kg were administered every 3 weeks until progression, unacceptable toxicity, or patient withdrawal. Primary endpoint was objective response rate (ORR) per RECIST 1.1. Exploratory biomarker analyses included PD-L1 expression on tumor (TC) and immune cells (IC), and spatial analysis of the immune infiltrate. Results: Sixty patients received at least 1 cycle of treatment, among whom 56 were evaluable for response (17 ccRCCsd and 39 NccRCC). ORR was 34% in the overall population, 53% in ccRCCsd and 26% in NccRCC. Median progression-free survival was 8.4 months (95%CI, 6.9-16.5). Baseline tumor tissue was available for 36 patients. TC PD-L1 expression ≥1% was associated with improved ORR (9/14, 64%) compared to patients with PD-L1 expression < 1% (4/20, 20%). Patients with TC PD-L1 expression ≥1% who experienced progressive disease as best response had shorter average distance between tumor cells and nearest neighboring immune cells at baseline. Further analysis of the immune tumor microenvironment on an expanded cohort, including IC PD-L1 expression and correlation with clinical outcomes, is ongoing and will be updated. Conclusions: The combination of atezolizumab plus bevacizumab is active in NccRCC and ccRCCsd. Candidate predictive biomarkers include PD-L1 expression in TC and topological analysis of the immune infiltrate. Clinical trial information: NCT02724878.

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Systematic analyses of the role of prognostic and immunological EIF3A, a reader protein, in clear cell renal cell carcinoma

Cancer Cell International ◽

10.1186/s12935-021-02364-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yi Zhang ◽

Xiaoliang Hua ◽

Haoqiang Shi ◽

Li Zhang ◽

Haibing Xiao ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Cells ◽

Renal Cell ◽

Clear Cell ◽

Multivariate Analyses ◽

Enrichment Analysis ◽

Marker Genes ◽

Cell Renal Cell Carcinoma ◽

Coexpressed Genes

Abstract Background Eukaryotic initiation factor 3a (EIF3A), a “reader” protein for RNA methylation, has been found to be involved in promoting tumorigenesis in a variety of cancers. The impact of EIF3A in clear cell renal cell carcinoma (ccRCC) has yet to be reported. This study aimed to identify the prognostic value of EIF3A in ccRCC and investigate the relationship between EIF3A expression and immune infiltration. Methods We collected 29 m6A-related mRNA data and clinicopathological parameters from The Cancer Genome Atlas (TCGA) database. Logistic regression analyses were used to analyse the correlation between EIF3A expression and clinical characteristics. Immunohistochemistry (IHC) was applied to examine EIF3A levels in normal and ccRCC tissues. Univariate and multivariate analyses were conducted to recognize independent factors associated with overall survival (OS) and disease-free survival (DFS). The nomogram aimed to predict the 1-, 3- and 5-year survival probabilities. Gene set enrichment analysis (GSEA) was carried out to determine the potential functions and related signalling pathways of EIF3A expression. To investigate EIF3A of coexpressed genes, we used LinkedOmics, and the results were subjected to enrichment analysis. Simultaneously, LinkedOmics and STRING datasets were used to identify EIF3A coexpressed genes that were visualized via Cytoscape. Finally, we evaluated whether EIF3A expression correlated with the infiltration of immune cells and the expression of marker genes in ccRCC by Tumour Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA). Result EIF3A expression was significantly different between ccRCC tissues and normal tissues. EIF3A expression was correlated with poor prognostic clinicopathological factors, and K–M analyses revealed that low EIF3A expression was correlated with a poor prognosis. The results of univariate and multivariate analyses proved that EIF3A was a prognostic factor in ccRCC patients. GSEA results indicated that EIF3A high expression was enriched in the renal cell carcinoma pathway. EIF3A expression was significantly positively correlated with B cells, CD8 + T cells, CD4 + T cells, neutrophils, macrophages, and dendritic cells. Furthermore, EIF3A expression was associated with most marker genes of immune cells. Conclusions EIF3A could serve as a potential biomarker for prognostic and diagnostic stratification of ccRCC and is related to immune cell infiltrates.

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The Immune-Related Gene HCST as a Novel Biomarker for the Diagnosis and Prognosis of Clear Cell Renal Cell Carcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.630706 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yongying Zhou ◽

Xiao Wang ◽

Weibing Zhang ◽

Huiyong Liu ◽

Daoquan Liu ◽

...

Keyword(s):

Gene Expression ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Immune Cells ◽

Renal Cell ◽

Clear Cell ◽

Signal Transducer ◽

Related Gene ◽

Cell Renal Cell Carcinoma ◽

Immune Related Gene

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney tumor worldwide. Analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases showed that the immune-related gene (IRG) hematopoietic cell signal transducer (HCST) could provide guidance for the diagnosis, prognosis, and treatment of ccRCC. The RNA-seq data of ccRCC tissues were extracted from two databases: TCGA (https://www.cancer.gov/about-nci/organization/ccg/research/structural-genomics/tcga) and GEO (https://www.ncbi.nlm.nih.gov/geo/). Corresponding clinical information was downloaded from TCGA. Immune-related gene data were extracted from the IMMPORT website (https://www.immport.org/). Differential analysis with R software (https://www.r-project.org/) was used to obtain a prognosis model of ccRCC IRGs. The differences were combined with the clinical data to assess the usefulness of the HCST as a prognostic biomarker. Based on data obtained from the Oncomine (https://www.oncomine.org/), Human Protein Atlas (https://www.proteinatlas.org/), and PubMed (https://pubmed.ncbi.nlm.nih.gov/) databases, the expression levels of the HCST in ccRCC, clinical-pathological indicators of relevance, and influence on prognosis were analyzed. Regulation of the HCST gene in ccRCC was assessed by gene set enrichment analysis (GSEA). In TCGA/GEO databases, the high HCST expression in tumor tissues was significantly correlated to the TMN stage, tumor grade, invasion depth, and lymphatic metastasis (p < 0.05). The overall survival (OS) of patients with high HCST gene expression was significantly lower than that of patients with low HCST gene expression (p < 0.001). Multivariate Cox regression analysis suggested that the HCST expression level [hazard ratio (HR) = 1.630, 95% confidence interval (CI) = 1.042–2.552], tumor cell grade (HR = 1.829, 95% CI = 1.115–3.001), and distant metastasis (HR = 2.634, 95%, CI = 1.562–4.442) were independent risk factors affecting the OS of ccRCC patients (all, p < 0.05). The GSEA study showed that there was significant enrichment in cell adhesion, tumorigenesis, and immune and inflammatory responses in HCST high expression samples. Hematopoietic cell signal transducer expression was closely associated with the levels of infiltrating immune cells around ccRCC tissues, especially dendritic cells (DCs). In conclusion, the present study suggested that the HCST was interrelated to the clinicopathology and poor prognosis of ccRCC. High HCST expression was also closely correlated with the levels of tumor-infiltrating immune cells, especially DCs.

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PD-L1 expression in non-clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.424 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 424-424 ◽

Cited By ~ 5

Author(s):

André P Fay ◽

Marcella Callea ◽

Kathryn P. Gray ◽

Thai Huu Ho ◽

Jiaxi Song ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Tumor Cells ◽

Immune Cells ◽

Renal Cell ◽

Clear Cell ◽

Multivariable Analysis ◽

Clinicopathological Features ◽

Cell Renal Cell Carcinoma ◽

Tumor Cell Membrane

424 Background: Programmed death-1 (PD-1) receptor negatively regulates T cell-mediated responses.PD-1 ligand (PD-L1) is aberrantly expressed in clear cell renal cell carcinoma (ccRCC) and is associated with worse prognosis. Levels of PD-L1 expressions in non-ccRCC and its association with clinicopathological features and survival are unknown. Methods: Formalin-fixed paraffin-embedded (FFPE) specimens were obtained from 97 patients with chromophobe (CHR), papillary (PAP), translocation Xp11.2 (TrL) RCC and oncoytoma (ONC) and were included in the analysis. PD-L1 expression was evaluated by immunohistochemistry using a mouse monoclonal anti-PD-L1 antibody (405.9A11). The assay was validated using FFPE cell line controls known to be positive or negative for PD-L1 expression by flow cytometry. PD-L1 tumor positivity (PD-L1+) was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in immune cells, a combined score based on the intensity of infiltrate and percentage of positive cells was used. Baseline characteristics including stage/grade, and survival data were collected. Comparisons between PD-L1 expression and clinicopathological features were evaluated using chisq or wilcoxon rank sum tests. Cox model tests for association of PD-L1 expression with OS in univariate and multivariable analysis. Results: Among 97 patients, 12 (12.4%) were considered PD-L1+ in tumor cells: 2/36 (5%) of CHR RCC, 5/50 (10%) of PAP RCC, 3/7 (43%) of TrL RCC, and 2/4 (50%) of ONC. PD-L1 positivity in tumor cells was significantly associated with higher stage (p=0.026) and grade (p=0.046), as well as lower OS on univariate (p=0.02) but not multivariate analysis (p=0.29). On the other hand, PD-L1 positivity by immune cells was observed in 50 (51.5%) patients: 13/36 (36%) of CHR RCC, 30/50 (60%) of PAP RCC, 6/7 (86%) of TrL RCC, and 1/4 (25%) of ONC. PD-L1 positivity in immune cells did not correlate with stage (p=0.7), grade (p=0.1) or OS (p=0.8). Conclusions: PD-L1 expression is variable in non-ccRCC and depends on histology and tumor vs. immune cells scoring. Only PD-L1 positivity in tumors cells was associated with aggressive features. Patients with non-ccRCC should not be automatically excluded from trials of agents that target the PD-1/PD-L1 pathway.

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