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Expression of ROR?t marks a pathogenic regulatory T cell subset in human colon cancer.

ABSTRACT: The role of regulatory T cells (T(regs)) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T(regs) have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T(reg) subsets. We report the preferential expansion of a T(reg) subset in human CC with potent T cell-suppressive, but compromised anti-inflammatory, properties; these cells are distinguished from T(regs) present in healthy donors by their coexpression of Foxp3 and ROR?t. T(regs) with similar attributes were found to be expanded in mouse models of hereditary polyposis. Indeed, ablation of the ROR?t gene in Foxp3(+) cells in polyp-prone mice stabilized T(reg) anti-inflammatory functions, suppressed inflammation, improved polyp-specific immune surveillance, and severely attenuated polyposis. Ablation of interleukin-6 (IL-6), IL-23, IL-17, or tumor necrosis factor-? in polyp-prone mice reduced polyp number but not to the same extent as loss of ROR?t. Surprisingly, loss of IL-17A had a dual effect: IL-17A-deficient mice had fewer polyps but continued to have ROR?t(+) T(regs) and developed invasive cancer. Thus, we conclude that ROR?t has a central role in determining the balance between protective and pathogenic T(regs) in CC and that T(reg) subtype regulates inflammation, potency of immune surveillance, and severity of disease outcome.

SUBMITTER: Blatner NR

PROVIDER: S-EPMC3762575 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.

Blatner Nichole R NR Mulcahy Mary F MF Dennis Kristen L KL Scholtens Denise D Bentrem David J DJ Phillips Joseph D JD Ham Soo S Sandall Barry P BP Khan Mohammad W MW Mahvi David M DM Halverson Amy L AL Stryker Steven J SJ Boller Anne-Marie AM Singal Ashima A Sneed Rebekka K RK Sarraj Bara B Ansari Mohammed Javeed MJ Oft Martin M Iwakura Yoichiro Y Zhou Liang L Bonertz Andreas A Beckhove Philipp P Gounari Fotini F Khazaie Khashayarsha K

Science translational medicine 20121201 164

The role of regulatory T cells (T(regs)) in human colon cancer (CC) remains controversial: high densities of tumor-infiltrating T(regs) can correlate with better or worse clinical outcomes depending on the study. In mouse models of cancer, T(regs) have been reported to suppress inflammation and protect the host, suppress T cells and protect the tumor, or even have direct cancer-promoting attributes. These different effects may result from the presence of different T(reg) subsets. We report the p ...[more]

PMID: 23241743

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Project description:BACKGROUND:Since the first evidence suggesting existence of stem-like cancer cells, the process of cells reprogramming to the stem cell state remains as an attractive tool for cancer stemness research. Current knowledge in the field of cancer stemness, indicates that the microenvironment is a fundamental regulator of cell behavior. With regard to this, we investigated the changes of genome wide gene expression in reprogrammed human colon normal epithelial CRL-1831 and colon carcinoma DLD1 cell lines grown under more physiologically relevant three-dimensional (3D) cell culture microenvironment compared to 2D monolayer. METHODS:Whole genome gene expression changes were evaluated in both cell lines cultured under 3D conditions over a 2D monolayer by gene expression microarray analysis. To evaluate the biological significance of gene expression changes, we performed pathway enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Gene network analysis was used to study relationships between differentially expressed genes (DEGs) in functional categories by the GeneMANIA Cytoscape toolkit. RESULTS:In total, we identified 3228 and 2654 differentially expressed genes (DEGs) for colon normal and cancer reprogrammed cell lines, respectively. Furthermore, the expression of 1097 genes was commonly regulated in both cell lines. KEGG enrichment analysis revealed that in total 129 and 101 pathways for iPSC-CRL-1831 and for CSC-DLD1, respectively, were enriched. Next, we grouped these pathways into three functional categories: cancer transformation/metastasis, cell interaction, and stemness. ?-catenin (CTNNB1) was confirmed as a hub gene of all three functional categories. CONCLUSIONS:Our present findings suggest common pathways between reprogrammed human colon normal epithelium (iPSC-CRL-1831) and adenocarcinoma (CSC-DLD1) cells grown under 3D microenvironment. In addition, we demonstrated that pathways important for cancer transformation and tumor metastatic activity are altered both in normal and cancer stem-like cells during the transfer from 2D to 3D culture conditions. Thus, we indicate the potential of cell culture models enriched in normal and cancer stem-like cells for the identification of new therapeutic targets in cancer treatment.

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Expression of ROR?t marks a pathogenic regulatory T cell subset in human colon cancer.

Publications

Expression of RORγt marks a pathogenic regulatory T cell subset in human colon cancer.

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