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Accumulation of tolerogenic human 6-sulfo LacNAc dendritic cells in renal cell carcinoma is associated with poor prognosis.

ABSTRACT: Dendritic cells (DCs) essentially contribute to the induction and regulation of innate and adaptive immunity. Based on these important properties, DCs may profoundly influence tumor progression in patients. However, little is known about the role of distinct human DC subsets in primary tumors and their impact on clinical outcome. In the present study, we investigated the characteristics of human 6-sulfo LacNAc (slan) DCs in clear cell renal cell carcinoma (ccRCC). slanDCs have been shown to display various tumor-directed properties and to accumulate in tumor-draining lymph nodes from patients. When evaluating 263 ccRCC and 227 tumor-free tissue samples, we found increased frequencies of slanDCs in ccRCC tissues compared to tumor-free tissues. slanDCs were also detectable in the majority of 24 metastatic lymph nodes and 67 distant metastases from ccRCC patients. Remarkably, a higher density of slanDCs was significantly associated with a reduced progression-free, tumor-specific or overall survival of ccRCC patients. Tumor-infiltrating slanDCs displayed an immature phenotype expressing interleukin-10. ccRCC cells efficiently impaired slanDC-induced T-cell proliferation and programming as well as natural killer (NK) cell activation. In conclusion, these findings indicate that higher slanDC numbers in ccRCC tissues are associated with poor prognosis. The induction of a tolerogenic phenotype in slanDCs leading to an insufficient activation of innate and adaptive antitumor immunity may represent a novel immune escape mechanism of ccRCC. These observations may have implications for the design of therapeutic strategies that harness tumor-directed functional properties of DCs against ccRCC.

SUBMITTER: Toma M

PROVIDER: S-EPMC4485722 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Accumulation of tolerogenic human 6-sulfo LacNAc dendritic cells in renal cell carcinoma is associated with poor prognosis.

Toma Marieta M Wehner Rebekka R Kloß Anja A Hübner Linda L Fodelianaki Georgia G Erdmann Kati K Füssel Susanne S Zastrow Stefan S Meinhardt Matthias M Seliger Barbara B Brech Dorothee D Noessner Elfriede E Tonn Torsten T Schäkel Knut K Bornhäuser Martin M Bachmann Michael P MP Wirth Manfred P MP Baretton Gustavo G Schmitz Marc M

Oncoimmunology 20150302 6

Dendritic cells (DCs) essentially contribute to the induction and regulation of innate and adaptive immunity. Based on these important properties, DCs may profoundly influence tumor progression in patients. However, little is known about the role of distinct human DC subsets in primary tumors and their impact on clinical outcome. In the present study, we investigated the characteristics of human 6-sulfo LacNAc (slan) DCs in clear cell renal cell carcinoma (ccRCC). slanDCs have been shown to disp ...[more]

PMID: 26155414

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Project description:ObjectiveClear cell renal cell carcinoma (ccRCC) is a malignant renal tumor that is highly prone to metastasis and recurrence. The exact pathogenesis of this cancer is still not well understood. This study aimed to identify novel hub genes in renal clear cell carcinoma and determine their diagnostic and prognostic value.MethodsIntersection genes were obtained from multiple databases, and protein-protein interaction analysis and functional enrichment analysis were performed to identify key pathways related to the intersection genes. Hub genes were identified using the cytoHubba plugin in Cytoscape. GEPIA and UALCAN were utilized to observe differences in mRNA and protein expression of hub genes between KIRC and adjacent normal tissues. The Wilcoxon rank sum test was used to analyze hub gene levels between paired KIRC and matched non-cancer samples. IHC results were obtained from the HPA online database, and according to the median gene expression level, they were divided into a high-expression group and a low-expression group. The correlation of these groups with the prognosis of KIRC patients was analyzed. Logistic regression and the Wilcoxon rank sum test were used to test the relationship between SLC34A1 level and clinicopathological features. The diagnostic value of SLC34A1 was evaluated by drawing the receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC). Cox regression analysis was used to analyze the relationship between clinicopathological features, SLC34A1 expression, and KIRC survival rate. LinkedOmics was used to obtain the genes most related to SLC34A1 and their functional enrichment. Genetic mutations and methylation levels of SLC34A1 in KIRC were obtained from the cBioPortal website and the MethSurv website, respectively.ResultsFifty-eight ccRCC differential genes were identified from six datasets, and they were mainly enriched in 10 functional items and 4 pathways. A total of 5 hub genes were identified. According to the GEPIA database analysis, low expression of SLC34A1, CASR, and ALDOB in tumors led to poor prognosis. Low expression of SLC34A1 mRNA was found to be related to clinicopathological features of patients. SLC34A1 expression in normal tissues could accurately identify tumors (AUC 0.776). SLC34A1 was also found to be an independent predictor of ccRCC in univariate and multivariate Cox analyses. The mutation rate of the SLC34A1 gene was 13%. Eight of the 10 DNA methylated CpG sites were associated with the prognosis of ccRCC. SLC34A1 expression in ccRCC was positively correlated with B cells, eosinophils, neutrophils, T cells, TFH, and Th17 cells, and negatively correlated with Tem, Tgd, and Th2 cells.ConclusionThe expression level of SLC34A1 in KIRC samples was found to be decreased, which predicted a decreased survival rate of KIRC. SLC34A1 may serve as a molecular prognostic marker and therapeutic target for KIRC patients.

Dataset Information

Accumulation of tolerogenic human 6-sulfo LacNAc dendritic cells in renal cell carcinoma is associated with poor prognosis.

Publications

Accumulation of tolerogenic human 6-sulfo LacNAc dendritic cells in renal cell carcinoma is associated with poor prognosis.

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