Aristolochic acid-related renal cell carcinoma exhibits a distinct tumor immune microenvironment and may be more responsive to immune checkpoint blockade
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE275422 | GEO | 2024/08/21
REPOSITORIES: GEO
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Project description:Although clear cell renal cell carcinoma (ccRCC) has been shown to result in widespread aberrant cytosine methylation and loss of 5-hydroxymethylcytosine (5hmC), the prognostic impact and therapeutic targeting of tis epigenetic aberrancy has not been fully explored. Analysis of 576 primary ccRCC samples demonstrated that loss of 5hmC was significantly associated with aggressive clinicopathologic features and was an independent adverse prognostic factor. Loss of 5hmC alsopredicted reduced progression-free survival after resection of nonmetastatic disease. The loss of 5hmC in ccRCC was not due to mutational or transcriptional inactivation of ten eleven translocation (TET) (4. AUTHOR: TET also appears as Tet. If these mean the same thing, choose one style to use throughout.) enzymes, but to their functional inactivation by l -2-hydroxyglutarate (L2HG), which was overexpressed due to the deletion and underexpression of L2HG dehydrogenase(L2HGDH). Ascorbic acid (AA) reduced methylation and restored genome-wide 5hmC levels via TET activation. Fluorescence quenching of the recombinant TET-2 protein was unaffected by L2HG in the presence of AA. Pharmacologic AA treatment led to reduced growth of ccRCC in vitro and reduced tumor growth in vivo, with increased intratumoral 5hmC. These data demonstrate that reduced 5hmC is associated with reduced survival in ccRCC and provide a preclinical rationale for exploring the therapeutic potential of high-dose AA in ccRCC.
2019-04-03 | GSE126823 | GEO
Project description:The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance though highly infiltrated by T cells. There is an urgent need to elucidate tumor immune evasion and to develop novel therapeutic target to boost the efficacy of immune checkpoint blockade (ICB) in RCC. Our study uncovers a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine2, 3dioxygenase1 (IDO1), a prospective candidate for immunotherapy. PABPC1L, markedly upregulated in RCC, correlates with unfavorable prognosis and resistance to ICB. Overexpressed PABPC1L bolsters tryptophan metabolism and induces T-cell dysfunction by stabilizing IDO1. Conversely, silencing PABPC1L diminishes IDO1 expression, mitigates cytotoxic T-cell suppression, and enhances responsiveness to anti-PD-1 therapy. Our findings underscore PABPC1L's crucial role in facilitating immune evasion in RCC, making it a potential addition to ICB therapy.
2024-02-14 | GSE241871 | GEO
Project description:The tumor microenvironment (TME) in renal cell carcinomas (RCC) is marked by substantial immunosuppression and immune resistance though highly infiltrated by T cells. There is an urgent need to elucidate tumor immune evasion and to develop novel therapeutic target to boost the efficacy of immune checkpoint blockade (ICB) in RCC. Our study uncovers a mechanism wherein the polyadenylate-binding protein PABPC1L modulates indoleamine2, 3dioxygenase1 (IDO1), a prospective candidate for immunotherapy. PABPC1L, markedly upregulated in RCC, correlates with unfavorable prognosis and resistance to ICB. Overexpressed PABPC1L bolsters tryptophan metabolism and induces T-cell dysfunction by stabilizing IDO1. Conversely, silencing PABPC1L diminishes IDO1 expression, mitigates cytotoxic T-cell suppression, and enhances responsiveness to anti-PD-1 therapy. Our findings underscore PABPC1L's crucial role in facilitating immune evasion in RCC, making it a potential addition to ICB therapy.
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Project description:Recently, we reported that expression of endogenous retroviruses (ERVs), a class of transposable element, is associated with response to immune checkpoint blockade (ICB) in renal cell carcinoma (RCC). Aberrant expression of ERVs can activate host antiviral responses, as well as produce neoantigens. ERV expression is repressed by DNA methylation and can be activated by DNA hypomethylating agents. Here, we investigate whether Decitabine, a DNA hypomethylating agent, can activate ERV expression and host antiviral defenses in RCC to potentially enhance response to ICB. Decitabine induced expression of ERV3-2 and ERV4700 in RCC cells lines, which was accompanied by activation of host antiviral defense genes and increased secretion of inflammatory cytokines. We validated this effect in primary human RCC cell lines. Knockout of RIG-I and MDA5 dsRNA sensors attenuated activation of antiviral responses associated with Decitabine treatment, and RIG-I and MDA5 immunoprecipitations showed increased ERV binding in RCC cells treated with Decitabine. Bioinformatic analysis of RNAseq data showed the Decitabine-induced gene signature could be associated with increased CD8 infiltration and response to ICB. Conditioned media from Decitabine treated RCC cells was capable of inducing host anti-viral defense in naïve RCC cells and could modestly improve activation of T-cells from healthy donors. Further, conditioned media from RCC cells treated with Decitabine significantly enhanced T-cell migration. In a small retrospective cohort of metastatic RCC patients treated with single-agent PD-1/PD-L1 blockade, activation of some host antiviral defense genes was significantly higher in responders compared with nonresponders. Thus, modulation of ERV expression by Decitabine to activate host antiviral defenses could represent a novel therapeutic strategy to enhance RCC patient response to immune checkpoint blockade.
2020-06-01 | GSE142381 | GEO
Project description:Aristolochic acid (AA) is a major ingredient in several Chinese herbs that exhibits a wide range of pharmacological effects. Recently, clinical reports and experimental studies have demonstrated that AA causes renal toxicities, acute renal failure and interstitial fibrosis.However, the molecular mechanism underlying AA nephrotoxicity is not yet fully understood. Embryonic stem cells (ESCs) are pluripotent cells isolated from early embryos, which have highly undifferentiated potential and are capable of differentiating into all kinds of body tissues and organs. It has been reported that ESCs are sensitive to drug stimulation, and thus may serve as important tools for in vitro assessment of drug toxicity. We aimed to identify accurate biomarkers of AA-induced renal toxicity on ESCs. Genomics analysis was performed to screen the changes in gene expression levels of ESCs following treatment with AA, in order to determine the potential biological processes in which AA induces renal toxicity.
2020-11-27 | GSE162195 | GEO
Project description:Aristolochic acid (AA) is a nephrotoxic carcinogen responsible for acute kidney injury, chronic renal failure, and associated urothelial cancers. This study aims to determine the genes in xenobiotic metabolism pathway regulated by AA and clarify the molecular mechanism underlying their action.
2018-05-09 | GSE101530 | GEO
Project description:Renal cell carcinoma (RCC) is among the ten most common malignancies. By far, the most common histology is clear cell (ccRCC). The Cancer Genome Atlas and other large scale sequencing studies of ccRCC have been integral to the current understanding of molecular events underlying RCC and its biology. However, these data sets have focused on primary RCC which often demonstrates indolent behavior. In contrast, metastatic disease is the major cause of mortality associated with ccRCC. However, data sets examining metastatic tumor are sparse. We therefore undertook an integrative analysis of gene expression and DNA methylome profiling of metastatic ccRCC in addition to primary RCC and normal kidney. Integrative analysis of the methylome and transcriptome identified over 30 RCC specific genes whose mRNA expression inversely correlated with promoter methylation including several known targets of hypoxia inducible factors (HIFs). Notably, genes encoding several metabolism-related proteins were identified as differentially regulated via methylation. Collectively, our data provide novel insight into biology of aggressive RCC. Furthermore, they demonstrate a clear role for epigenetics in the promotion of HIF signaling and invasive phenotypes in renal cancer.
2018-10-16 | GSE105288 | GEO
Project description:Purpose: Renal cell carcinoma (RCC) is often diagnosed incidentally as an early-stage small renal mass (SRM; pT1a, ≤ 4 cm). Increasing concerns surrounding the overtreatment of patients with benign or clinically indolent tumors has led to a shift in current treatment recommendations, especially for elderly and infirm patients. There are currently no available biomarkers to accurately stratify patients according to risk. Therefore, we set out to identify early biomarkers of RCC progression. Experimental Design: We employed label-free LC-MS/MS and targeted parallel-reaction monitoring (PRM) to identify early, non-invasive diagnostic and prognostic biomarkers for early-stage RCC-SRMs. In total, we evaluated 115 urine samples, including 33 renal oncocytoma (≤ 4 cm) cases, 30 progressive and 26 non-progressive clear cell RCC-SRM (ccRCC-SRM) cases, in addition to 26 healthy controls. Results: We identified nine endogenous peptides which displayed significantly elevated expression in ccRCC-SRMs relative to healthy controls. Peptides NVINGGSHAGNKLAMQEF, VNVDEVGGEALGRL, and VVAGVANALAHKYH showed significantly elevated expression in ccRCC-SRMs relative to renal oncocytoma. Additionally, peptides SHTSDSDVPSGVTEVVVKL and IVDNNILFLGKVNRP displayed significantly elevated expression in progressive relative to non-progressive ccRCC-SRMs. Peptide SHTSDSDVPSGVTEVVVKL showed the most significant discriminatory ability (AUC: 0.76, 95% CI: 0.62 to 0.90, p = 0.0027). Patients with elevated SHTSDSDVPSGVTEVVVKL expression had significantly shorter overall survival (HR: 4.13, 95% CI: 1.09 to 15.65, p = 0.024) compared to patients with lower expression. Conclusions: Our in-depth peptidomic analysis identified novel biomarkers for early-stage RCC-SRMs. Characterization of urinary peptides may provide insight into early RCC progression and could potentially help assign patients to appropriate management programs.
2019-08-08 | PXD013111 | Pride
Project description:Renal cell carcinoma (RCC) is one of the most common cancers worldwide with nearly non-symptomatic course till advanced stage of disease. RCC can be distinguished into three subtypes: papillary (pRCC), chromophobe (chRCC) and clear cell renal cell carcinoma (ccRCC) representing up to 75% of all RCC cases. Detection and RCC monitoring tools are limited to standard imaging techniques, in combination with non-RCC specific morphological and biochemical read-outs. RCC subtype identification relays mainly on results of pathological examination of tumor slides. Molecular, clinically applicable and ideally non-invasive tools aiding RCC management are still non-existent, although molecular characterization of RCC is relatively advanced. Hence many research efforts concentrate on identification of molecular markers that will assist with RCC sub-classification and monitoring. Due to stability and tissue-specificity miRNAs are promising candidates for such biomarkers. Here we performed a meta-analysis study, utilized seven available NGS and seven microarray RCC studies in order to identify subtype-specific expression of miRNAs. We concentrated on four potentially oncocytoma-specific miRNAs (miRNA-424-5p, miRNA-146b-5p, miRNA-183-5p, miRNA-218-5p), two pRCC (miRNA-127-3p, miRNA-139-5p) and eight ccRCC specific miRNAs (miRNA-200c-3p, miRNA-362-5p, miRNA-363-3p and miRNA-204-5p, 21-5p, miRNA-224-5p, miRNA-155-5p, miRNA-210-3p) and validated their expression in an independent sample set. Additionally, we found ccRCC-specific miRNAs to be differentially expressed in ccRCC Fuhrman grades and identified alterations in their isoform composition in tumor tissue. Our results revealed that changes in expression of selected miRNA might be potentially utilized as a tool aiding ccRCC subclass discrimination and propose a miRNA panel aiding RCC subtype distinction.
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Project description:Renal cell carcinoma (RCC) is one of the most common cancers worldwide with nearly non-symptomatic course till advanced stage of disease. RCC can be distinguished into three subtypes: papillary (pRCC), chromophobe (chRCC) and clear cell renal cell carcinoma (ccRCC) representing up to 75% of all RCC cases. Detection and RCC monitoring tools are limited to standard imaging techniques, in combination with non-RCC specific morphological and biochemical read-outs. RCC subtype identification relays mainly on results of pathological examination of tumor slides. Molecular, clinically applicable and ideally non-invasive tools aiding RCC management are still non-existent, although molecular characterization of RCC is relatively advanced. Hence many research efforts concentrate on identification of molecular markers that will assist with RCC sub-classification and monitoring. Due to stability and tissue-specificity miRNAs are promising candidates for such biomarkers. Here we performed a meta-analysis study, utilized seven available NGS and seven microarray RCC studies in order to identify subtype-specific expression of miRNAs. We concentrated on four potentially oncocytoma-specific miRNAs (miRNA-424-5p, miRNA-146b-5p, miRNA-183-5p, miRNA-218-5p), two pRCC (miRNA-127-3p, miRNA-139-5p) and eight ccRCC specific miRNAs (miRNA-200c-3p, miRNA-362-5p, miRNA-363-3p and miRNA-204-5p, 21-5p, miRNA-224-5p, miRNA-155-5p, miRNA-210-3p) and validated their expression in an independent sample set. Additionally, we found ccRCC-specific miRNAs to be differentially expressed in ccRCC Fuhrman grades and identified alterations in their isoform composition in tumor tissue. Our results revealed that changes in expression of selected miRNA might be potentially utilized as a tool aiding ccRCC subclass discrimination and propose a miRNA panel aiding RCC subtype distinction.
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