ObjectiveThe nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis.DesignTissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of CD19, CD8A, IFNG was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study.ResultsTumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-γ, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells.ConclusionsThe close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC.
Aneuploidy is a key process in tumorigenesis. Dysfunction of the mitotic spindle checkpoint proteins has been implicated as a cause of aneuploidy in cells. We have previously reported that FAT10, a member of the ubiquitin-like modifier family of proteins, is overexpressed in several gastrointestinal and gynecological cancers. Here we show that FAT10 interacts with MAD2, a spindle checkpoint protein, during mitosis. Notably, we show that localization of MAD2 at the kinetochore during the prometaphase stage of the cell cycle was greatly reduced in FAT10-overexpressing cells. Furthermore, compared with parental HCT116 cells, fewer mitotic cells were observed after double thymidine-synchronized FAT10-overexpressing cells were released into nocodazole for more than 4 h. Nonetheless, when these double thymidine-treated cells were released into media, a similar number of G 1 parental and FAT10-overexpressing HCT116 cells was observed throughout the 10-h time course. Additionally, more nocodazole-treated FAT10-overexpressing cells escape mitotic controls and are multinucleate compared with parental cells. Significantly, we observed a higher degree of variability in chromosome number in cells overexpressing FAT10. Hence, our data suggest that high levels of FAT10 protein in cells lead to increased mitotic nondisjunction and chromosome instability, and this effect is mediated by an abbreviated mitotic phase and the reduction in the kinetochore localization of MAD2 during the prometaphase stage of the cell cycle. Genetic instability is an important phenomenon that underlies tumorigenesis. Chromosome instability (CIN)2 involving gains and loss of chromosomes has been found to occur in most malignancies, whereas microsatellite instability, which occurs at the nucleotide level, is less commonly observed in cancers (1). Two forms of CIN, namely structural instability and numerical instability (aneuploidy), can be observed in various tumors. Genes responsible for CIN in human cancers include those involved in the condensation of chromosomes, cohesion of sister chromatids, formation of microtubules, and kinetochore structure and function as well as mitotic "checkpoint" genes that monitor the proper progression through the cell cycle (1, 2).MAD2 (mitotic arrest-deficient 2) is a key mitotic spindle checkpoint protein whose primary role is to ensure that all of the chromosomes are properly attached to the mitotic spindle before the onset of anaphase (3). It is activated by associating with unattached kinetochores. Activated MAD2 binds to Cdc20 and prevents the anaphase-promoting complex from ubiquitylating securin. As a result, anaphase is delayed until all of the kinetochores are attached by microtubules and the chromosomes are properly aligned along the metaphase plate (4 -6). MAD2 is an essential gene, and MAD2 Ϫ/Ϫ mice die in utero (7). Loss of one allele of MAD2 has been reported to result in premature anaphase and CIN in mammalian cells (8). Dysregulation of MAD2 has been implicated in various cancers. Reduced expression of ...
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