The collaboration of both humoral and cellular HER-2/neu-targeted immune responses is required for the complete eradication of HER-2/neu-expressing tumors.
HER-2/neu (neu) transgenic mice (neu-N mice), which express the nontransforming rat proto-oncogene, demonstrate immunological tolerance to neu that is similar to what is encountered in patients with neu-expressing breast cancer. We have shown previously that a significant increase in neu-specific T cells, but no induction of neu-specific antibody, is seen after neu-specific vaccination in neu-N mice. In contrast, a significant induction of both neu-specific T-cell and antibody responses is found in nontoleragenic FVB/N mice after vaccination. These mice are fully protected from a s.c. challenge with NT cells, a mammary tumor cell line derived from a spontaneous tumor that arose in a neu-N mouse, whereas neu-N mice are not. In this study, we demonstrate that CD4+ T cell-depleted FVB/N mice show no induction of neu-specific IgG after vaccination and are unable to reject an NT challenge (0 of 10 mice were tumor free). Conversely, the depletion of natural killer cells has no effect on vaccine-mediated tumor rejection (100% of mice were tumor free). In CD8+ T cell-depleted animals, where vaccine-induced neu-specific IgG titers were normal, NT growth was delayed, but only 10% of mice remained tumor free, demonstrating that neu-specific IgG alone is insufficient for protection from NT challenge. To directly assess the necessity for the combination of neu-specific cellular and humoral immune responses, severe combined immunodeficient mice were given an adoptive transfer of CTLs plus IgG derived from FVB/N mice. Animals that were given CTLs that recognized an irrelevant antigen plus neu-specific IgG developed tumors at a rate similar to CD8+ T cell-depleted FVB/N mice. Animals receiving an adoptive transfer of neu-specific CTLs plus control IgG derived from naive FVB/N mice were only partially protected from NT challenge (50% of animals were tumor free). However, only animals receiving the combination of neu-specific CTLs and neu-specific IgG were fully protected from NT challenge (100% of animals were tumor free). These studies specifically define the immunological requirements for the eradication of neu-expressing tumors in this model system, demonstrating that both cellular and humoral neu-specific responses are necessary for protection from an NT challenge. These data suggest that vaccines optimized to induce maximal T- and B-cell immunity to neu, and possibly to similar putative tumor-rejection antigens, may lead to more potent in vivo antitumor immunity.
Reilly
R T
RT
Department of Oncology, The Johns Hopkins School of Medicine, Baltimore, Maryland 21231, USA.
Machiels
J P
JP
Emens
L A
LA
Ercolini
A M
AM
Okoye
F I
FI
Lei
R Y
RY
Weintraub
D
D
Jaffee
E M
EM
D016475:3T3 Cells / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination
D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases