Tumor cell surface display of immunoglobulin heavy chain Fc by gene transfer as a means to mimic antibody therapy.
We hypothesized that inducing display of the immunoglobulin Fc (IgFc) molecule on the tumor cell surface by gene transfer would promote tumor cell killing by the same mechanisms as antibody-based approaches but would alleviate some of the problems inherent in the use of antibodies for cancer therapy. We expressed the cDNA of the Fc portion of the murine IgG2a heavy chain on the surface of tumor cells such that its C terminus projected away from the tumor cell surface, mimicking a natural antibody-tagging event. In vitro, Fc receptor-positive natural killer (NK) cells specifically recognized and lysed B16 melanoma cells expressing surface IgFc. Macrophages bound to B16-Fc cells significantly more than to parental B16 cells and surface IgFc expression promoted formation of the terminal complement pore complex leading to cell lysis and death. Expression of IgFc dramatically delayed the ability of B16 cells to form tumors in vivo, attributable largely to the effects of NK cells. Furthermore, fluorescence-activated cell-sorting analysis showed that cells from outgrowth B16 IgFc tumors had lost all IgFc expression. When additional immunostimulatory signals were provided at the time of IgFc-mediated tumor cell killing through expression of heat shock protein 70 (hsp70), significant antitumor immunity was generated. Intratumoral delivery of an adenoviral vector expressing IgFc was effective at treating locally accessible tumors but did not impact metastatic disease. However, delivery of adenoviral vectors expressing both IgFc and hsp70 cured both local and metastatic tumors established for 6 days before viral treatment. These data suggest that it is possible to use gene transfer to mimic the beneficial properties of antibody therapy while alleviating some of the associated problems.
Riddle
David S
DS
Molecular Medicine Program and Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Sanz
Laura
L
Chong
Heung
H
Thompson
Jill
J
Vile
Richard G
RG
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019496:Cancer Vaccines; D002460:Cell Line; D002478:Cells, Cultured; D003167:Complement Activation; D003602:Cytotoxicity, Immunologic; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D007116:Immunization, Passive; D007141:Immunoglobulin Fc Fragments / Q000235:genetics* / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis; D014162:Transfection
D019496:Cancer Vaccines; D007141:Immunoglobulin Fc Fragments; D007143:Immunoglobulin Heavy Chains