T he dendritic cell (DC) plays a central role in orchestrating cellular immune responses to self and foreign antigens. A process of ''maturation'' that occurs after the acquisition of antigen results in up-regulation of MHC͞peptide and costimulatory ligands on the surface of DCs and in the secretion of immunomodulatory cytokines. In the mature state the DC is primed to activate T cells in an antigen-specific fashion. DC maturation is not, however, a consequence of antigen acquisition per se. Exposure to substances within the tissue microenvironment regulate DC maturational events. Among the factors that induce DC maturation are components of pathogenic microorganisms, products secreted by parenchymal cells and macrophages, and contact with activated T cells (1-6). Whether the preservation of DCs in an immature state results from the absence of maturational stimuli or is also actively maintained is not known.We
Microtubule-depolymerizing agents are widely used to synchronize cells, screen for mitotic checkpoint defects, and treat cancer. The present study evaluated the effects of these agents on normal and malignant human breast cell lines. After treatment with 1 μM nocodazole, seven of ten breast cancer lines (type A cells) arrested in mitosis, whereas the other three (type B cells) did not. Similar effects were observed with 100 nM vincristine or colchicine. Among five normal mammary epithelial isolates, four exhibited type A behavior and one exhibited type B behavior. Further experiments revealed that the type B cells exhibited a biphasic dose-response curve, with mitotic arrest at low drug concentrations (100 nM nocodazole or 6 nM vincristine) that failed to depolymerize microtubules and a p53-independent p21waf1/cip1-associated G1 and G2 arrest at higher concentrations (1 μM nocodazole or 100 nM vincristine) that depolymerized microtubules. Collectively, these observations provide evidence for coupling of premitotic cell-cycle progression to microtubule integrity in some breast cancer cell lines (representing a possible “microtubule integrity checkpoint”) and suggest a potential explanation for the recently reported failure of some cancer cell lines to undergo nocodazole-induced mitotic arrest despite intact mitotic checkpoint proteins
Fusion of tumor cells with antigen-presenting cells (APCs) has been proposed for the preparation of cancer vaccines. However, generation of these hybrids, using physical or chemical methods such as electrofusion or polyethylene glycol (PEG), has been difficult to standardize. Characterization of cell fusion has also been problematic because of difficulties in differentiating fusion from cell aggregation, leakage of cellular dyes and dendritic-cell (DC) phagocytosis of tumor material. In this report, we describe a new method to generate hybrid cell vaccines, based on gene transfer of a viral fusogenic membrane glycoprotein (FMG) into tumor cells, and incorporate a genetic method by which true hybrid formation can be unambiguously detected. We describe a new class of tumor cell-DC hybrid that can be rapidly isolated after cell fusion. These hybrids are highly potent in in vitro antigen presentation assays, target lymph nodes in vivo and are powerful immunogens against established metastatic disease.
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