Identification of Immune-Related Subtypes and Characterization of Tumor Microenvironment Infiltration in Kidney Renal Clear Cell Carcinoma
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ABSTRACT:
SUBMITTER: Qin H
PROVIDER: S-EPMC9277187 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIt is well known that chronic inflammation can promote the occurrence and progression of cancer. As a type of proinflammatory death, pyroptosis can recast a suitable microenvironment to promote tumor growth. However, the potential role of pyroptosis in clear cell renal cell carcinoma (ccRCC) remains unclear.MethodsThe transcriptome expression profile and mutation profile data of ccRCC with clinical characteristics included in this study were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Consensus clustering was used for clustering. Gene set enrichment analysis (GSEA) analysis were applied to evaluate the biological mechanisms. Single sample gene set enrichment analysis (ssGSEA) was applied for evaluating the proportion of various immune infiltrating cells. The ESTIMATE algorithm was involved to compute the immune microenvironment scores.ResultsAmong the 17 pyroptosis regulators, a total of 15 pyroptosis regulators were differential expressed between tumor and normal tissues, in which 12 of them emerged strong correlations with prognoses. According to the pyroptosis components, the ccRCC patients were divided into four pyroptosis subtypes with different clinical, molecular, and pathway characteristics. Compared with other clusters, cluster B showed the pyroptosis heat phenotype, while cluster D represented the pyroptosis cold phenotype with poor overall survival. In addition, we performed principal component analysis (PCA) on the differential genes between clusters to construct the pyroptosis index. Furthermore, the pyroptosis index was significantly correlated with survival in different tumor mutation statuses and different grades and stages. Besides, the expression of pyroptosis-related regulators was related to the infiltration of immune cells and the expression of immune checkpoints, among which AIM2 was considered as the most significant immune-related pyroptosis regulator. Ultimately, we found that AIM2 was related to the immune activation pathway and was significantly overexpressed in tumor tissues.ConclusionThis study revealed that pyroptosis regulators and pyroptosis index played an important role in the development and prognoses of ccRCC. Moreover, AIM2 can be used as a predictor of the response of immunotherapy. Assessing the pyroptosis patterns may help evaluate the tumor status and guide immunotherapy strategies.
| S-EPMC8766752 | biostudies-literature
Project description:Copper toxicity involves the destruction of mitochondrial metabolic enzymes, triggering an unusual mechanism of cell death called cuproptosis, which proposes a novel approach using copper toxicity to treat cancer. However, the biological function of cuproptosis has not been fully elucidated in kidney renal clear cell carcinoma (KIRC). Using the expression profile of 13 cuproptosis regulators, we first identified two molecular subtypes related to cuproptosis defined as "hot tumor" and "cold tumor", having different levels of biological function, clinical prognosis, and immune cell infiltration. We obtained three gene clusters using the differentially expressed genes between the two cuproptosis-related subtypes, which were associated with different molecular activities and clinical characteristics. Next, we developed and validated a cuproptosis prognostic model that included two genes (FDX1 and DBT). The calculated risk score could divide patients into high- and low-risk groups. The high-risk group had a poorer prognosis, lower level of immune infiltration, higher frequency of gene alterations, and greater levels of FDX1 methylation and limited DBT methylation. The risk score was also an independent predictive factor for overall survival in KIRC. The established nomogram calculating the risk score achieved a high predictive ability for the prognosis of individual patients (area under the curve: 0.860). We then identified small molecular inhibitors as potential treatments and analyzed the sensitivity to chemotherapy of the signature genes. Tumor immune dysfunction and exclusion (TIDE) showed that the high-risk group had a higher level of TIDE, exclusion and dysfunction that was lower than the low-risk group, while the microsatellite instability of the high-risk group was significantly lower. The results of two independent immunotherapy datasets indicated that cuproptosis regulators could influence the response and efficacy of immunotherapy in KIRC. Our study provides new insights for individualized and comprehensive therapy of KIRC.
| S-EPMC9635053 | biostudies-literature
Project description:Increasing evidence suggests the essential regulation of RNA N6-methyladenosine (m6A) modification in carcinogenesis and immune response. Nevertheless, the potential impacts of these modifications on the tumor microenvironment (TME) immune cell infiltration characteristics in clear-cell renal cell carcinoma (ccRCC) remain unclear. Utilizing a consensus clustering algorithm, we determined three m6A modification patterns and identified three m6A-related gene clusters among 569 ccRCC samples, which were associated with different biological functions and clinical outcomes. Thereafter, the m6A score was constructed using m6A-associated signature genes to accurately exploit the m6A modification patterns within individual tumors. The m6A score was further demonstrated to be noticeably related to ccRCC prognosis. In addition, the m6A score was found to be strongly correlated with tumor mutational burden (TMB), microsatellite instability, immune infiltration, immune checkpoint expression, and immunotherapy response, which was also validated in the pan-cancer analyses. Our findings thoroughly elucidated that m6A modification contributes to tumor microenvironment immune-infiltrating characteristics and prognosis in ccRCC. Assessing the m6A modification patterns of individual patients with ccRCC will offer novel insights into TME infiltration and help develop more effective treatment strategies.
| S-EPMC9068873 | biostudies-literature
Project description:The incidence of kidney renal clear cell carcinoma (KIRC) is rising worldwide, and the prognosis is poor. Cuproptosis is a new form of cell death that is dependent on and regulated by copper ions. The relationship between cuproptosis and KIRC remains unclear. In the current study, changes in cuproptosis-related genes (CRGs) in TCGA-KIRC transcriptional datasets were characterized, and the expression patterns of these genes were analyzed. We identified three main molecular subtypes and discovered that multilayer CRG changes were associated with patient clinicopathological traits, prognosis, elesclomol sensitivity, and tumor microenvironment (TME) cell infiltration characteristics. Then, a CRG score was created to predict overall survival (OS). The CRG score was found to be strongly linked to the TME. These findings may help elucidate the roles of CRGs in KIRC, potentially enhancing understanding of cuproptosis and supporting the development of more effective immunotherapy strategies.
| S-EPMC9299088 | biostudies-literature
Project description:Current treatment strategy for kidney renal clear cell carcinoma (KIRC) is limited. Tumor-associated antigens, especially neoantigen-based personalized mRNA vaccines represent new strategies and manifest clinical benefits in solid tumors, but only a small proportion of patients could benefit from them, which prompts us to identify effective antigens and suitable populations to facilitate mRNA vaccines application in cancer therapy. Through performing expression, mutation, survival and correlation analyses in TCGA-KIRC dataset, we identified four genes including DNA topoisomerase II alpha (TOP2A), neutrophil cytosol factor 4 (NCF4), formin-like protein 1 (FMNL1) and docking protein 3 (DOK3) as potential KIRC-specific neoantigen candidates. These four genes were upregulated, mutated and positively associated with survival and antigen-presenting cells in TCGA-KIRC. Furthermore, we identified two immune subtypes, named renal cell carcinoma immune subtype 1 (RIS1) and RIS2, of KIRC. Distinct clinical, molecular and immune-related signatures were observed between RIS1 and RIS2. Patients of RIS2 had better survival outcomes than those of RIS1. Further comprehensive immune-related analyses indicated that RIS1 is immunologically "hot" and represent an immunosuppressive phenotype, whereas RIS2 represents an immunologically "cold" phenotype. RIS1 and RIS2 also showed differential features with regard to tumor infiltrating immune cells and immune checkpoint-related genes. Moreover, the immune landscape construction identified the immune cell components of each KIRC patient, predicted their survival outcomes, and assisted the development of personalized mRNA vaccines. In summary, our study identified TOP2A, NCF4, FMNL1 and DOK3 as potential effective neoantigens for KIRC mRNA vaccine development, and patients with RIS2 tumor might benefit more from mRNA vaccination.
| S-EPMC8645676 | biostudies-literature
Project description:BackgroundGRAM structural domain-containing protein 1A (GRAMD1A) is upregulated in a variety of human cancer tissues and is closely associated with tumourigenesis and progression.MethodsPatient RNA-sequencing data and clinicopathological information were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. The expression of GRAMD1A in kidney cancer cell lines and KIRC patients was analysed by quantitative polymerase chain reaction (qPCR). Receiver Operator Characteristic (ROC) curves, nomograms, Kaplan-Meier analysis, forest plots, and COX analysis were used to assess the diagnostic and prognostic value of GRAMD1A in KIRC, and gene set enrichment analysis (GSEA) was used to explore its potential signalling pathways. In addition, the Sangerbox website, Kaplan-Meier plotter database, and TISIDB and TIMER databases were used to further analyse the correlation of GRAMD1A with microsatellite instability (MSI), tumour mutational burden (TMB), immune checkpoint genes, and tumour-infiltrating lymphocytes (TILs).ResultsGRAMD1A was significantly highly expressed in KIRC and associated with shorter overall survival and relapse-free survival (P < 0.05). The AUC value of the ROC curve to identify KIRC and normal renal tissues was 0.942. Forest plot and COX analysis visualized that GRAMD1A could be an independent prognostic factor in KIRC patients (P < 0.01), and nomograms to determine the overall survival (OS) of KIRC patients also showed good efficacy (C-index: 0.776). Moreover, Spearman correlation analysis showed a positive correlation between GRAMD1A and MSI, TMB (P < 0.01). On the other hand, GRAMD1A was also found to be closely associated with immune checkpoint genes. Meanwhile, patients with KIRC with high GRAMD1A expression had a relatively low hazard ratio (HR) of death when B lymphocytes, natural killer T cells, CD4+ T lymphocytes, CD8+ T lymphocytes, and macrophages were enriched in the tumour microenvironment (TME), and a greater HR of death when regulatory T lymphocytes with tumour-specific immunosuppressive effects were significantly enriched. Last, GSEA shows that GRAMD1A is closely associated with the regulation of energy metabolism in KIRC.ConclusionsGRAMD1A is a promising diagnostic and prognostic biomarker for patients with KIRC, and its biological function correlates to some extent with immune infiltration in TME.
| S-EPMC9293538 | biostudies-literature
Project description:Growing evidence has highlighted the immune response as an important feature of carcinogenesis and therapeutic efficacy in clear cell renal cell carcinoma (ccRCC). This study categorized ccRCC cases into high and low score groups based on their immune/stromal scores generated by the ESTIMATE algorithm, and identified an association between these scores and prognosis. Differentially expressed tumor environment (TME)-related genes extracted from common upregulated components in immune and stromal scores were described using functional annotations and protein-protein interaction (PPI) networks. Most PPIs were selected for further prognostic investigation. Many additional previously neglected signatures, including AGPAT9, AQP7, HMGCS2, KLF15, MLXIPL, PPARGC1A, exhibited significant prognostic potential. In addition, multivariate Cox analysis indicated that MIXIPL and PPARGC1A were the most significant prognostic signatures, and were closely related to immune infiltration in TCGA cohort. External prognostic validation of MIXIPL and PPARGC1A was undertaken in 380 ccRCC cases from a real-world cohort. These findings indicate the relevance of monitoring and manipulation of the microenvironment for ccRCC prognosis and precision immunotherapy.
| S-EPMC6756904 | biostudies-literature
Project description:Objective: Because of the modest immunotherapeutic response among ovarian carcinoma (OC) patients, it is significant to evaluate antitumor immune response and develop more effective precision immunotherapeutic regimens. Here, this study aimed to determine diverse immune subtypes of OC. Methods: This study curated the expression profiles of prognostic immunologically relevant genes and conducted consensus clustering analyses for determining immune subtypes among OC patients in TCGA cohort. With Boruta algorithm, characteristic genes were screened for conducting an immune scoring system through principal component analysis algorithm. The single-sample gene set enrichment analysis and ESTIAMTE methods were adopted for quantifying the immune infiltrates and responses to chemotherapeutic agents were estimated with pRRophetic algorithm. Two immunotherapeutic cohorts were used for investigating the efficacy of immune score in predicting therapeutic benefits. Results: Two immune subtypes were conducted among 377 OC patients. Immune subtype 2 was characterized by worse clinical prognosis, more frequent genetic variations and mutations, enhanced immune infiltrates, and increased expression of MHC molecules and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1). In total, 30 prognosis-relevant characteristic immune subtype-derived genes were identified for constructing the immune score of OC patients. High immune score was linked with more dismal prognosis, decreased immune infiltrations, and expression of MHC molecules. High immune score presented favorable sensitivity to doxorubicin and vinorelbine and reduced sensitivity to cisplatin. In addition, immune score possessed the potential in predicting benefits from anti-PD-1/PD-L1 therapy. Conclusion: Collectively, our findings propose two complex and diverse immune subtypes of OC. Quantitative assessment of immune subtypes in individual patients strengthens the understanding of tumor microenvironment features and promotes more effective immunotherapeutic regimens.
| S-EPMC8977982 | biostudies-literature
Project description:Anoikis is a specific form of programmed cell death induced by the loss of cell contact with the extracellular matrix and other cells, and plays an important role in organism development, tissue homeostasis, disease development and tumor metastasis. We comprehensively investigated the expression patterns of anoikis-related genes (ARGs) in kidney renal clear cell carcinoma (KIRC) from public databases. Anoikis-related prognostic signatures were established based on four ARGs expression, in which KIRC patients were assigned different risk scores and divided into two different risk groups. In addition, four ARGs expression was validated by qRT-PCR. A better prognosis was observed in the low-risk group, but with lower immune activity (including immune cells and immune-related functions) in the tumor microenvironment. Combined with the relevant clinical characteristics, a nomogram for clinical application was established. Receiver operating characteristics (ROC) and calibration curves were constructed to demonstrate the predictive power of this risk signature. In addition, higher risk scores were significantly and positively correlated with higher gene expression of tumor mutation load (TMB), immune checkpoints (ICPs) and mismatch repair (MMR)-related proteins in general. The results also suggested that the high-risk group was more sensitive to immunotherapy and certain chemotherapeutic agents. Anoikis-related prognostic signatures may provide a better understanding of the roles of ARGs and offer new perspectives for clinical prognosis and individualized treatment.
| S-EPMC10593771 | biostudies-literature
Project description:Tumors are closely related to the tumor microenvironment (TME). The complex interaction between tumor cells and the TME plays an indisputable role in tumor development. Tumor cells can affect the TME, promote tumor angiogenesis and induce immune tolerance by releasing cell signaling molecules. Immune cell infiltration (ICI) in the TME can affect the prognosis of patients with bladder cancer. However, the pattern of ICI of the TME in bladder cancer has not yet been elucidated. Herein, we identified three distinct ICI subtypes based on the TME immune infiltration pattern of 584 bladder cancer patients using the ESTIMATE and CIBERSORT algorithms. Then, we identified three gene clusters based on the differentially expressed genes (DEGs) between the three ICI subtypes. In addition, the ICI score was determined using single sample gene set enrichment analysis (ssGSEA). The results suggested that patients in the high ICI score subgroup had a favorable prognosis and higher expression of checkpoint-related and immune activity-related genes. The high ICI score subgroup was also linked to increased tumor mutation burden (TMB) and neoantigen burden. A cohort treated with anti-PD-L1 immunotherapy confirmed the therapeutic advantage and clinical benefit of patients with higher ICI scores. In the end, our study also shows that the ICI score represents an effective prognostic predictor for evaluating the response to immunotherapy. In conclusion, our study deepened the understanding of the TME, and it provides new ideas for improving patients' response to immunotherapy and promoting individualized tumor immunotherapy in the future.
| S-EPMC8438153 | biostudies-literature