Identification for prognostic value of differentially expressed genes in immune microenvironment of clear cell renal cell carcinoma

Abstract Background: Genes related to Anchorimmune microenvironment of clear cell renal cell carcinoma (ccRCC) remains unclear. We aimed to identify related to immune microenvironment and to screen the most significant genes to predict outcomes of ccRCC. Methods: Gene expression and clinicopathological data from TCGA data portal were obtained (KIRC). Immune and stromal scores were calculated based on ESTIMATE algorithm. DEGs between low and high groups of immune scores were identified. Subsequent functional enrichment analysis and protein-protein interaction of DEGs were conducted by DAVID database. Results: Patients were divided into low and high groups by medians according to immune (median: 1038.45) and stromal scores (median: 667.945), respectively. Immune scores were significantly correlated with clinicopathological parameters and overall survival (OS). Based on immune scores, 1433 genes were up-regulated, and among them, 890 DEGs were significantly associated with OS. Based on top 10 DEGs, cases with number of up-regulated genes ≥5 were associated poor OS (P = 0.002). In addition, the mean differences of percentages of CD8 T cells (11.32%), CD4 memory resting T cells (-4.52%) and mast resting cells (-3.55%) between low and high immune scores were the most significant. Conclusions: A list of immune microenvironment-related genes in ccRCC was initially identified, and high immune score was an independent poor prognostic factor of OS. Furthermore, the combination of these genes might use to predict the efficacy of immunotherapy. Further analyses of these genes were warrant to explore their potential association with the prognosis of ccRCC.

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Prognostic implications of Aquaporin 9 expression in clear cell renal cell carcinoma

Journal of Translational Medicine ◽

10.1186/s12967-019-2113-y ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 3

Author(s):

Wen-Hao Xu ◽

Shen-Nan Shi ◽

Yue Xu ◽

Jun Wang ◽

Hong-Kai Wang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Prognostic Value ◽

Clear Cell ◽

Roc Curves ◽

Functional Enrichment ◽

Clinicopathological Parameters ◽

Cell Renal Cell Carcinoma ◽

Aquaporin 9

Abstract Background Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients. Methods A total of 913 ccRCC patients with available RNA-sequence data from the Cancer Genome Atlas (TCGA) database and Fudan University Shanghai Cancer Center (FUSCC) were consecutively recruited in analyses. Differential transcriptional and proteome expression profiles were obtained and validated using multiple datasets. A partial likelihood test from Cox regression analysis was developed to address the influence of independent factors on progression-free survival (PFS) and overall survival (OS). The Kaplan–Meier method and log-rank test were performed to assess survival. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of AQP9 using area under the curve (AUC) score. Functional enrichment analyses and immune infiltration analysis were used to describe significantly involved hallmark pathways of hub genes. Results Significantly elevated transcriptional and proteomic AQP9 expressions were found in ccRCC samples. Increased AQP9 mRNA expression was significantly associated with advanced clinicopathological parameters and correlated with shorter PFS and OS in TCGA and FUSCC cohorts (p < 0.001). ROC curves suggested the significant diagnostic and prognostic ability of AQP9 (PFS, AUC = 0.823; OS, AUC = 0.828). Functional annotations indicated that AQP9 is involved in the most significant hallmarks including complement, coagulation, IL6/JAK–STAT3, inflammatory response and TNF-alpha signaling pathways. Conclusion Our study revealed that elevated AQP9 expression was significantly correlated with aggressive progression, poor survival and immune infiltrations in ccRCC patients, and we validated its prognostic value in a real-world cohort. These data suggest that AQP9 may act as an oncogene and a promising prognostic marker in ccRCC.

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A Novel Immune-Related lncRNA-Based Model for Survival Prediction in Clear Cell Renal Cell Carcinoma

Journal of Immunology Research ◽

10.1155/2021/9921466 ◽

2021 ◽

Vol 2021 ◽

pp. 1-37

Author(s):

Zedan Zhang ◽

Yanlin Tang ◽

Yanjun Liu ◽

Hongkai Zhuang ◽

Enyu Lin ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

T Cells ◽

Cell Carcinoma ◽

Renal Cell ◽

Cox Regression ◽

Clear Cell ◽

Functional Enrichment ◽

Clinical Parameters ◽

Training Set ◽

Cell Renal Cell Carcinoma

Background. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer whose incidence and mortality rate are increasing. Identifying immune-related lncRNAs and constructing a model would probably provide new insights into biomarkers and immunotherapy for ccRCC and aid in the prognosis prediction. Methods. The transcription profile and clinical information were obtained from The Cancer Genome Atlas (TCGA). Immune-related gene sets and transcription factor genes were downloaded from GSEA website and Cistrome database, respectively. Tumor samples were divided into the training set and the testing set. Immune-related differentially expressed lncRNAs (IDElncRNAs) were identified from the whole set. Univariate Cox regression, LASSO, and stepwise multivariate Cox regression were performed to screen out ideal prognostic IDElncRNAs (PIDElncRNAs) from the training set and develop a multi-lncRNA signature. Results. Consequently, AC012236.1, AC078778.1, AC078950.1, AC087318.1, and AC092535.4 were screened to be significantly related to the prognosis of ccRCC patients, which were used to establish the five-lncRNA signature. Its wide diagnostic capacity was revealed in different subgroups of clinical parameters. Then AJCC-stage, Fuhrman-grade, pharmaceutical, age, and risk score regarded as independent prognostic factors were integrated to construct a nomogram, whose good performance in predicting 3-, 5-, and 7-year overall survival of ccRCC patients was revealed by time-dependent ROC curves and verified by the testing sets and ICGC dataset. The calibration plots showed great agreement of the nomogram between predicted and observed outcomes. Functional enrichment analysis showed the signature and each lncRNA were mainly enriched in pathways associated with regulation of immune response. Several kinds of tumor-infiltrating immune cells like regulatory T cells, T follicular helper cells, CD8+ T cells, resting mast cells, and naïve B cells were significantly correlated with the signature. Conclusion. Therefore, we constructed a five-lncRNA model integrating clinical parameters to help predict the prognosis of ccRCC patients. The five immune-related lncRNAs could potentially be therapeutic targets for immunotherapy in ccRCC in the future.

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Systematic exploration of prognostic alternative splicing events related to immune microenvironment of Clear Cell Renal Cell Carcinoma

10.21203/rs.3.rs-1138551/v1 ◽

2021 ◽

Author(s):

Youyuan Deng ◽

Jianguo Wang ◽

Yanrui Pang ◽

Jingyong Li ◽

Huaixiao Zhang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Alternative Splicing ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Functional Enrichment ◽

Immune Microenvironment ◽

Cell Renal Cell Carcinoma ◽

Systematic Exploration ◽

Immune Score

Abstract Background Clear cell renal cell carcinoma (ccRCC) accounts for almost 75% of all renal cancers, with high heterogeneity and poor prognosis. There is increasing evidence that alternative splicing (AS) is associated with tumorigenesis and immune microenvironment. However, studies on the relationship between AS events and immunity in ccRCC are still few but needed. Methods The transcriptional data and clinicopathological information of ccRCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. We grouped patients according to the ESTIMATE algorithm and identified for differentially expressed AS events (DEASs). The functional enrichment analysis and unsupervised consensus analysis were performed to investigate the association between AS events and immune features. The regulatory network of survival-related AS events and intersection SFs was used to explore potential mechanisms. Results In total, 515 ccRCC patients were included in the present study. The low immune-score group had longer overall survival (OS) than the high low immune-score group. 861 AS events were identified as DEASs, and they were enriched in immune-related pathways. Unsupervised clustering analysis revealed that AS-based clusters significantly corelated with prognosis and immune features of ccRCC. Finally, MBNL1 was identified as a hub SF, and it was shown to inhibit proliferation and metastasis, promote apoptosis, and block cells in G2/M phase in 786O and A498 cells. Conclusion The present systematic exploration elaborated that not only some critical AS events were related to prognosis and immune microenvironment of ccRCC, but also the hub SF, such as MBNL1, could affect the development and progression of ccRCC.

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Comprehensive analysis of pyroptosis regulators and tumor immune microenvironment in clear cell renal cell carcinoma

Cancer Cell International ◽

10.1186/s12935-021-02384-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yan Zhang ◽

Xianwu Chen ◽

Qinghe Fu ◽

Feifan Wang ◽

Xuejian Zhou ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

T Cells ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Gene Set Enrichment Analysis ◽

Immune Microenvironment ◽

Cell Renal Cell Carcinoma ◽

Tumor Immune Microenvironment ◽

Cluster 2

Abstract Background Increasing evidence has indicated that pyroptosis could regulate the tumor immune microenvironment (TIME) to affect the tumor development. As a highly immunogenic tumor, clear cell renal cell carcinoma (ccRCC) can benefit from immunotherapy, but related research on pyroptosis in the TIME of ccRCC is still deficient. Methods Available data derived from TCGA and GEO databases were analyzed to identify the different expression profiles of pyroptosis in ccRCC and normal tissues, and the correlation of pyroptosis regulators with TIME was evaluated in ccRCC. Results According to consensus clustering analysis, two differential expression levels of subtypes were identified to affect patient prognosis, and were related to histological tumor stage and grade. Immune cells were calculated by the CIBERSORT algorithm. Higher infiltrated levels of B cells naive, T cells CD4 memory resting, NK cells resting, monocytes, macrophages were observed in Cluster 1, while higher infiltrated levels of CD8+ T cells, T follicular helper cells, and Tregs were observed in Cluster 2. Gene set enrichment analysis indicated that Cluster 2 was enriched in multiple immune-related pathways, including the JAK-STAT signaling pathway. Moreover, overexpression of eight immune checkpoints was related to ccRCC development, especially in Cluster 2. As four potentially key pyroptosis regulators, AIM2, CASP5, NOD2, and GZMB were confirmed to be upregulated in ccRCC by RT-qPCR analysis and further verified by the HPA database. Further pan-cancer analysis suggested that these four pyroptosis regulators were differentially expressed and related to the TIME in multiple cancers. Conclusion The present study provided a comprehensive view of pyroptosis regulators in the TIME of ccRCC, which may provide potential value for immunotherapy.

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Tumor infiltrating and peripheral CD4+ILT2+ T cells are a cytotoxic subset selectively inhibited by HLA-G in clear cell renal cell carcinoma patients

Cancer Letters ◽

10.1016/j.canlet.2021.06.018 ◽

2021 ◽

Author(s):

Alix Jacquier ◽

Tiphaine Lambert ◽

Jean-François Delattre ◽

Malika Djouadou ◽

Jérôme Vérine ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

T Cells ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma

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Tumor-infiltrating CD8+ T cells recognize a heterogeneously expressed functional neoantigen in clear cell renal cell carcinoma

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-03048-6 ◽

2021 ◽

Author(s):

Masahiro Matsuki ◽

Yoshihiko Hirohashi ◽

Munehide Nakatsugawa ◽

Aiko Murai ◽

Terufumi Kubo ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

T Cells ◽

Cell Carcinoma ◽

Cd8 T Cells ◽

Renal Cell ◽

Clear Cell ◽

Cell Renal Cell Carcinoma

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Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma

10.1101/2021.03.19.21253661 ◽

2021 ◽

Author(s):

Lewis Au ◽

Emine Hatipoglu ◽

Marc Robert de Massy ◽

Kevin Litchfield ◽

Andrew Rowan ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

T Cells ◽

Cell Carcinoma ◽

Cd8 T Cells ◽

Renal Cell ◽

Clear Cell ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus ◽

Cell Renal Cell Carcinoma ◽

Pre Treatment

Antigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naive patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+ T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+ T-cells to enhance cytotoxicity.

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Systematic Analyses of The Role of Prognostic And Immunological of EIF3A, A Reader Protein, In Clear Cell Renal Cell Carcinoma

10.21203/rs.3.rs-696657/v1 ◽

2021 ◽

Author(s):

Yi Zhang ◽

Xiaoliang Hua ◽

Haoqiang Shi ◽

Li Zhang ◽

HaiBing Xiao ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

T Cells ◽

Cell Carcinoma ◽

Immune Cells ◽

Renal Cell ◽

Clear Cell ◽

Multivariate Analyses ◽

Enrichment Analysis ◽

Marker Genes ◽

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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