Dataset Information

Regulatory T-cells and associated pathways in metastatic renal cell carcinoma (mRCC) patients undergoing DC-vaccination and cytokine-therapy.

ABSTRACT:

Purpose

To evaluate CD4(+)CD25(+)FOXP3(+) T regulatory cells (T(REG)) and associated immune-regulatory pathways in peripheral blood lymphocytes (PBL) of metastatic renal cell carcinoma (mRCC) patients and healthy volunteers. We subsequently investigated the effects of immunotherapy on circulating T(REG) combining an extensive phenotype examination, DNA methylation analysis and global transcriptome analysis.

Design

Eighteen patients with mRCC and twelve volunteers (controls) were available for analysis. T(REG) phenotype was examined using flow cytometry (FCM). T(REG) were also quantified by analyzing the epigenetic status of the FOXP3 locus using methylation specific PCR. As a third approach, RNA of the PBL was hybridized to Affymetrix GeneChip Human Gene 1.0 ST Arrays and the gene signatures were explored using pathway analysis.

Results

We observed higher numbers of T(REG) in pre-treatment PBL of mRCC patients compared to controls. A significant increase in T(REG) was detected in all mRCC patients after the two cycles of immunotherapy. The expansion of T(REG) was significantly higher in non-responders than in responding patients. Methylation specific PCR confirmed the FCM data and circumvented the variability and subjectivity of the FCM method. Gene Set Enrichment Analysis (GSEA) of the microarray data showed significant enrichment of FOXP3 target genes, CTLA-4 and TGF-ß associated pathways in the patient cohort.

Conclusion

Immune monitoring of the peripheral blood and tumor tissue is important for a wide range of diseases and treatment strategies. Adoption of methodology for quantifying T(REG) with the least variability and subjectivity will enhance the ability to compare and interpret findings across studies.

SUBMITTER: Schwarzer A

PROVIDER: S-EPMC3485261 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

Regulatory T-cells and associated pathways in metastatic renal cell carcinoma (mRCC) patients undergoing DC-vaccination and cytokine-therapy.

Schwarzer Adrian A Wolf Benita B Fisher Jan L JL Schwaab Thomas T Olek Sven S Baron Udo U Tomlinson Craig R CR Seigne John D JD Crosby Nancy A NA Gui Jiang J Hampton Thomas H TH Fadul Camilo E CE Heaney John A JA Ernstoff Marc S MS

PloS one 20121031 10

<h4>Purpose</h4>To evaluate CD4(+)CD25(+)FOXP3(+) T regulatory cells (T(REG)) and associated immune-regulatory pathways in peripheral blood lymphocytes (PBL) of metastatic renal cell carcinoma (mRCC) patients and healthy volunteers. We subsequently investigated the effects of immunotherapy on circulating T(REG) combining an extensive phenotype examination, DNA methylation analysis and global transcriptome analysis.<h4>Design</h4>Eighteen patients with mRCC and twelve volunteers (controls) were a ...[more]

PMID: 23118856

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Project description:BACKGROUND:International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium (IMDC) risk groups are important when considering therapeutic options for first-line treatment. MATERIALS AND METHODS:Adult patients with clear cell mRCC initiating first-line sunitinib between 2010 and 2018 were included in this retrospective database study. Median time to treatment discontinuation (TTD) and overall survival (OS) were estimated using Kaplan-Meier analysis. Outcomes were stratified by IMDC risk groups and evaluated for those in the combined intermediate and poor risk group and separately for those in the intermediate risk group with one versus two risk factors. RESULTS:Among 1,769 patients treated with first-line sunitinib, 318 (18%) had favorable, 1,031 (58%) had intermediate, and 420 (24%) had poor IMDC risk. Across the three risk groups, patients had similar age, gender, and sunitinib initiation year. Median TTD was 15.0, 8.5, and 4.2 months in the favorable, intermediate, and poor risk groups, respectively, and 7.1 months in the combined intermediate and poor risk group. Median OS was 52.1, 31.5, and 9.8 months in the favorable, intermediate, and poor risk groups, respectively, and 23.2 months in the combined intermediate and poor risk group. Median OS (35.1 vs. 21.9 months) and TTD (10.3 vs. 6.6 months) were significantly different between intermediate risk patients with one versus two risk factors. CONCLUSION:This real-world study found a median OS of 52 months for patients with favorable IMDC risk treated with first-line sunitinib, setting a new benchmark on clinical outcomes of clear cell mRCC. Analysis of intermediate risk group by one or two risk factors demonstrated distinct clinical outcomes. IMPLICATIONS FOR PRACTICE:This analysis offers a contemporary benchmark for overall survival (median, 52.1 months; 95% confidence interval, 43.4-61.2) among patients with clear cell metastatic renal cell carcinoma who were treated with sunitinib as first-line therapy in a real-world setting and classified as favorable risk according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group classification. This study demonstrates that clinical outcomes differ between IMDC risk groups as well as within the intermediate risk group based on the number of risk factors, thus warranting further consideration of risk group when counseling patients about therapeutic options and designing clinical trials.

Project description:BackgroundNivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted.MethodsPatients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered "feasible" if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval.ResultsOf the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16-53) off therapy. No patients developed RECIST PD while off therapy.ConclusionsThis prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC.Trial registrationNCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331 ).

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Project description:Purpose: To investigate the potential mechanisms contributing to metastasis of clear cell renal cell carcinoma (ccRCC), screen the hub genes, associated pathways of metastatic ccRCC and identify potential biomarkers. Methods: The ccRCC metastasis gene expression profile GSE47352 was employed to analyze the differentially expressed genes (DEGs). DAVID was performed to assess Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The protein-protein interaction (PPI) network and modules were constructed. The function pathway, prognostic and diagnostic analysis of these hub genes was picked out to estimate their potential effects on metastasis of ccRCC. Results: A total of 873 DEGs were identified (503 upregulated genes and 370 downregulated genes). Meanwhile, top 20 hub genes were displayed. GO analysis showed that the top 20 hub genes were enriched in regulation of phosphatidylinositol 3-kinase signaling, positive regulation of DNA replication, protein autophosphorylation, protein tyrosine kinase activity, etc. KEGG analysis indicated these hub genes were enriched in the Ras signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, Pathways in cancer, etc. The GO and KEGG enrichment analyses for the hub genes disclosed important biological features of metastatic ccRCC. PPI network showed the interaction of top 20 hub genes. Gene Set Enrichment Analysis (GSEA) revealed that some of the hub genes was associated with metastasis, epithelial mesenchymal transition (EMT), hypoxia cancer and adipogenesis of ccRCC. Some top hub genes were distinctive and new discoveries compared with that of the existing associated researches. Conclusions: Our analysis uncovered that changes in signal pathways such as Ras signaling pathway, PI3K-Akt signaling pathway, etc. may be the main signatures of metastatic ccRCC. We identified several candidate biomarkers related with overall survival (OS) and disease-free survival (DFS) of ccRCC patients. Accordingly, they might be novel therapeutic targets and used as potential biomarkers for diagnosis, prognosis of ccRCC.

Dataset Information

Regulatory T-cells and associated pathways in metastatic renal cell carcinoma (mRCC) patients undergoing DC-vaccination and cytokine-therapy.

Purpose

Design

Results

Conclusion

Publications

Regulatory T-cells and associated pathways in metastatic renal cell carcinoma (mRCC) patients undergoing DC-vaccination and cytokine-therapy.

Similar Datasets

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