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IFN-λ inhibits HCV replication and triggers IFN-dependent genes. We hypothesized that IFN-λ is immunomodulatory and evaluated its effects on myeloid dendritic cells (DC). DCs generated with IFN-λ (IFN-λ-DC) expressed normal levels of DC markers, but showed reduced allostimulatory capacity in mixed lymphocyte reaction (MLR), similar to DCs of patients with chronic HCV infection (HCV-DC). No additive effects of IFN-λ subtypes were observed. The inhibition of MLR was due to preferential expansion of CD4+CD25+ T cells in the presence of HCV-DCs or IFN-λ-DC, but not normal DCs. Purified CD4+CD25+ T cells from MLR were Foxp3+, CD45RA+, produced IL-10 and TGFb, and inhibited CD4+CD25− T cell proliferation. HCV-DCs produced increased levels of IFN-λ compared to controls. In vitro generation of DCs in the presence of LPS increased expression of IFN-λ. Interestingly, we found increased plasma levels of LPS in HCV patients compared to controls suggesting a possible in vivo mechanism for IFN-λ induction. Further, in vitro DCs generation with LPS resulted in expansion of Tregs and inhibition of MLR, thus mimicking the effects of HCV-DCs and IFN-λ-DCs. We also identified an increased frequency of Tregs in peripheral blood of HCV patients (12±2%) compared to controls (5±1%) (p

One of the hallmarks of cancer is chromosomal instability, which leads to aneuploidy, translocations, loss of heterozygosity, and other chromosomal aberrations. Chromosomal instability is an early event in cancer pathogenesis and is thought to help generate the large number of genetic lesions required for a cell to undergo malignant transformation. It has been hypothesized that this instability is due to inactivating mutations in genes that control the mitotic checkpoint and chromosome segregation. However, in the vast majority of human tumors the molecular basis of chromosomal instability and the aneuploidy it produces remains unknown. We have recently identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors (Science 333:1039, 2011). A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer. These findings and additional unpublished observations regarding the role of STAG2 inactivation in aneuploidy will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3114. doi:1538-7445.AM2012-3114