Lipofection indirectly increases expression of endogenous major histocompatibility complex class I molecules on tumor cells.
Direct intratumoral injection of a lipid/DNA complex encoding an allogeneic major histocompatibility complex (MHC) class I molecule leads to regression of both an immunogenic murine tumor and also melanoma lesions in some patients. We have sought to understand the mechanism(s) for this augmentation of antitumor activity. While optimizing parameters for in vitro gene transfer into the D5 subclone of B16BL6, it was noted that lipofected tumors not only expressed the new alloantigen but also exhibited increased expression of endogenous MHC class I, both H-2 Kb and H-2 Db. This increase in expression was not restricted to the small percentage of cells that expressed the transfected gene, but appeared to affect the majority of cells in culture. Class I expression was not increased by lipopolysaccharide, DNA alone, lipid, or lipid/lipopolysaccharide mixtures. Enhanced class I expression required a DNA/lipid complex and was greatest when parameters optimized for gene transfer of the alloantigen were used. All DNA plasmids tested had this effect, including one plasmid whose DNA was not transcribed because it lacked an expression cassette. Because of the critical role that MHC class I antigens play in immune recognition, we propose that lipid complex-mediated gene transfer may provide immunological advantages beyond those that are attributable to expression of the specific gene transferred.
Fox
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Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center, Oregon 97213, USA. foxb@ohsu.edu
Drury
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Hu
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Cao
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Huntzicker
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Qie
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Urba
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D000818:Animals; D004247:DNA / Q000737:chemistry / Q000494:pharmacology; D018014:Gene Transfer Techniques; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism*; D008055:Lipids / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D051379:Mice; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation
D006183:H-2 Antigens; C024755:H-2K(K) antigen; C032876:H-2Kb protein, mouse; D064532:Histocompatibility Antigen H-2D; D015395:Histocompatibility Antigens Class I; D008055:Lipids; D008070:Lipopolysaccharides; D004247:DNA