Nonredundant roles of antibody, cytokines, and perforin in the eradication of established Her-2/neu carcinomas.
Since the mechanisms by which specific immunity destroys Her-2/neu carcinoma cells are highly undetermined, these were assessed in BALB/c mice vaccinated with plasmids encoding extracellular and transmembrane domains of the protein product (p185(neu)) of the rat Her-2/neu oncogene shot into the skin by gene gun. Vaccinated mice rejected a lethal challenge of TUBO carcinoma cells expressing p185(neu). Depletion of CD4 T cells during immunization abolished the protection, while depletion of CD8 cells during the effector phase halved it, and depletion of polymorphonuclear granulocytes abolished all protection. By contrast, Ig mu-chain gene KO mice, as well as Fcgamma receptor I/III, beta-2 microglobulin, CD1, monocyte chemoattractant protein 1 (MCP1), IFN-gamma, and perforin gene KO mice were protected. Only mice with both IFN-gamma and perforin gene KOs were not protected. Although immunization also cured all BALB/c mice bearing established TUBO carcinomas, it did not cure any of the perforin KO or perforin and IFN-gamma KO mice. Few mice were cured that had knockouts of the gene for Ig mu-chain, Fcgamma receptor I/III, IFN-gamma, or beta-2 microglobulin. Moreover, vaccination cured half of the CD1 and the majority of the MCP1 KO mice. The eradication of established p185(neu) carcinomas involves distinct mechanisms, each endowed with a different curative potential.
Curcio
Claudia
C
Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy.
Di Carlo
Emma
E
Clynes
Raphael
R
Smyth
Mark J
MJ
Boggio
Katia
K
Quaglino
Elena
E
Spadaro
Michela
M
Colombo
Mario P
MP
Amici
Augusto
A
Lollini
Pier-Luigi
PL
Musiani
Piero
P
Forni
Guido
G
D000818:Animals; D000912:Antibodies, Neoplasm / Q000502:physiology*; D019470:Biolistics; D019496:Cancer Vaccines / Q000276:immunology*; D016207:Cytokines / Q000502:physiology*; D005260:Female; D006084:Graft Rejection; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*
D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D008562:Membrane Glycoproteins; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA