Early role of CD4+ Th1 cells and antibodies in HER-2 adenovirus vaccine protection against autochthonous mammary carcinomas.
HER-2 is an oncogenic tumor-associated Ag that is overexpressed in several human tumors including breast and ovarian cancer. The efficacy and mechanism of a HER-2-expressing recombinant adenoviral vaccine to protect against tumorigenesis was examined using HER-2 transgenic (BALB-neuT) mice, which develop spontaneous breast tumors in all 10 mammary glands, and also using a transplantable mouse tumor model. Vaccination beginning at 6-8 wk of age (through 19 wk of age) prevented development of spontaneous mammary tumors even after 50 wk, whereas the animals in the control groups had tumors in all mammary glands by 25 wk. Such long-term protection after the last boost has not been achieved previously in this transgenic mouse in which the oncogene is continuously spawning tumorigenesis. Using beta(2)-microglobulin-knockout, IFN-gamma-knockout, and B cell-deficient mice, CD4(+) and CD8(+) cell depletion, and Ab transfer studies, we show that induction of anti-HER-2/neu Abs are both necessary and sufficient for protection, and the IgG2a isotype is most effective. In contrast, CD8(+) T cells are not necessary at all, and CD4(+) T cells are necessary for only 36-48 h after immunization to provide help for B cells but not as effector cells. Equal protection in immunized mice deficient in FcgammaRI/III excluded an FcR-mediated mechanism. Anti-HER-2 serum not only inhibited growth of mammary tumor cell lines expressing HER-2 in vitro but also protected mice from tumors in vivo, suggesting a direct action of Ab on the tumor cells. Such a vaccine may provide Ab-mediated protection against HER-2-expressing breast cancers in humans.
Park
Jong Myun
JM
Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Terabe
Masaki
M
Sakai
Yoshio
Y
Munasinghe
Jeeva
J
Forni
Guido
G
Morris
John C
JC
Berzofsky
Jay A
JA
D000256:Adenoviridae; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000592:standards; D005260:Female; D007074:Immunoglobulin G; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage* / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D013997:Time Factors
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases