Dataset Information

Tumor-infiltrating Leukocytes Suppress Local Inflammation Via Interleukin-1 Receptor Antagonist in a Syngeneic Prostate Cancer Model.

ABSTRACT: BACKGROUND:Several lines of evidence have demonstrated the tumor-promoting function of inflammation. Since many chemokines are important in coordinating immune cells during inflammation, monitoring intratumoral chemokines provides a way to study the tumor microenvironment. METHODS:To identify tumorigenic chemokines, we compared two syngeneic mouse prostate cancer cell lines by an antibody array and quantitative reverse-transcription polymerase chain reaction (RT-PCR). The tumor microenvironment was analyzed by monitoring gene expressions in mouse tumor tissues, primary cells, and tumor-infiltrating leukocytes (TILs). RESULT:We identified a group of pro-inflammatory chemokines associated with a tumorigenic transgenic adenocarcinoma mouse prostate (TRAMP)-C1 cell line. In the tumor microenvironment, the TILs secrete a natural anti-inflammatory factor, interleukin-1 receptor antagonist (IL1RN), which inhibits the functions of pro-inflammatory molecules and likely accounts for tumor type-specific anti-inflammation functions. CONCLUSION:Our results support that tumor cells recruit TILs by pro-inflammatory chemokines to establish an IL1RN-mediated anti-inflammatory environment in the syngeneic prostate cancer model.

SUBMITTER: Fan YC

PROVIDER: S-EPMC7235745 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Tumor-infiltrating Leukocytes Suppress Local Inflammation Via Interleukin-1 Receptor Antagonist in a Syngeneic Prostate Cancer Model.

Fan Yu-Ching YC Chen Wei-Yu WY Lee Kuan-Der KD Tsai Yuan-Chin YC

Biology 20200331 4

<h4>Background</h4>Several lines of evidence have demonstrated the tumor-promoting function of inflammation. Since many chemokines are important in coordinating immune cells during inflammation, monitoring intratumoral chemokines provides a way to study the tumor microenvironment.<h4>Methods</h4>To identify tumorigenic chemokines, we compared two syngeneic mouse prostate cancer cell lines by an antibody array and quantitative reverse-transcription polymerase chain reaction (RT-PCR). The tumor mi ...[more]

PMID: 32244522

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Project description:BackgroundAssays of the abundance of immune cell populations in the tumor microenvironment promise to inform immune oncology research and the choice of immunotherapy for individual patients. We propose to measure the intratumoral abundance of various immune cell populations with gene expression. In contrast to IHC and flow cytometry, gene expression assays yield high information content from a clinically practical workflow. Previous studies of gene expression in purified immune cells have reported hundreds of genes showing enrichment in a single cell type, but the utility of these genes in tumor samples is unknown. We use co-expression patterns in large tumor gene expression datasets to evaluate previously reported candidate cell type marker genes lists, eliminate numerous false positives and identify a subset of high confidence marker genes.MethodsUsing a novel statistical tool, we use co-expression patterns in 9986 samples from The Cancer Genome Atlas (TCGA) to evaluate previously reported cell type marker genes. We compare immune cell scores derived from these genes to measurements from flow cytometry and immunohistochemistry. We characterize the reproducibility of our cell scores in replicate runs of RNA extracted from FFPE tumor tissue.ResultsWe identify a list of 60 marker genes whose expression levels measure 14 immune cell populations. Cell type scores calculated from these genes are concordant with flow cytometry and IHC readings, show high reproducibility in replicate RNA samples from FFPE tissue and enable detailed analyses of the anti-tumor immune response in TCGA. In an immunotherapy dataset, they separate responders and non-responders early on therapy and provide an intricate picture of the effects of checkpoint inhibition. Most genes previously reported to be enriched in a single cell type have co-expression patterns inconsistent with cell type specificity.ConclusionsDue to their concise gene set, computational simplicity and utility in tumor samples, these cell type gene signatures may be useful in future discovery research and clinical trials to understand how tumors and therapeutic intervention shape the immune response.

Project description:IL1-RN is an important anti-inflammatory cytokine that modulate the inflammation response by binding to IL1 receptors, and as a consequence inhibits the action of proinflammatory cytokines IL1alpha and IL1beta. In this study, we hypothesise that sequence variants in the IL1-RN gene are associated with prostate cancer risk. The study population, a population-based case-control study in Sweden, consisted of 1383 prostate cancer case patients and 779 control subjects. We first selected 18 sequence variants covering the IL1-RN gene and genotyped these single-nucleotide polymorphisms (SNPs) in 96 control subjects. Gene-specific haplotypes of IL1-RN were constructed and four haplotype-tagging single-nucleotide polymorphisms (htSNPs) were identified (rs878972, rs315934, rs3087263 and rs315951) that could uniquely describe >95% of the haplotypes. All study subjects were genotyped for the four htSNPs. No significant difference in genotype frequencies between cases and controls were observed for any of the four SNPs based on a multiplicative genetic model. Overall there was no significant difference in haplotype frequencies between cases and controls; however, the prevalence of the most common haplotype (ATGC) was significantly higher among cases (38.7%) compared to controls (33.5%) (haplotype-specific P = 0.009). Evaluation of the prostate cancer risk associated with carrying the 'ATGC' haplotype revealed that homozygous carriers were at significantly increased risk (odds ratio (OR) = 1.6, 95% confidence interval (CI) = 1.2-2.2), compared to noncarriers, while no significant association was found among subjects heterozygous for the haplotype (OR = 1.0, 95% CI = 0.8-1.2). Restricting analyses to advanced prostate cancer strengthened the association between the 'ATGC' haplotype and disease risk (OR for homozygous carriers vs noncarriers 1.8, 95% CI = 1.3-2.5). In conclusion, the results from this study support the hypothesis that inflammation has a role of in the development of prostate cancer, but further studies are needed to identify the causal variants in this region and to elucidate the biological mechanism for this association.

Dataset Information

Tumor-infiltrating Leukocytes Suppress Local Inflammation Via Interleukin-1 Receptor Antagonist in a Syngeneic Prostate Cancer Model.

Publications

Tumor-infiltrating Leukocytes Suppress Local Inflammation Via Interleukin-1 Receptor Antagonist in a Syngeneic Prostate Cancer Model.

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