Antibody-dependent natural killer cell-mediated cytotoxicity engendered by a kinase-inactive human HER2 adenovirus-based vaccination mediates resistance to breast tumors.
Cancer vaccines may have applications in the therapy and prevention of mammary carcinoma. To investigate such applications, we constructed a recombinant adenoviral vaccine expressing a kinase-inactive mutant form of human HER2 and introduced this into BALB/c wild-type (WT) or HER2 transgenic mice. Here, we report contributions by antibody responses and natural killer (NK) cells in tumor protection in this model. One i.p. vaccination protected WT mice from the HER2-expressing mouse carcinoma D2F2/E2. Half of the HER2 transgenic mice were protected fully and long term after preventive vaccination. Tumor growth in mice that eventually developed neoplastic lesions was delayed. Protection in WT and HER2 transgenic mice was associated with high or low levels of IgG2a antibodies, respectively, whereas CTLs were observed in WT but not in HER2 transgenic mice. Depleting CD4(+) or CD8(+) cells in vaccinated WT mice had limited effects, suggesting that protection was largely independent of CD4(+) or CD8(+) T cells. In contrast, antibody-mediated tumor rejection seemed to contribute significantly based on a loss of protection in mice deficient for Fc-γ RI/III or B cells. Further, a role for antibody-dependent cellular cytotoxicity (ADCC) mediated by NK cells was indicated by evidence that vaccine protection could be abolished by in vivo depletion of NK cells. Lastly, NK cells and immune sera purified from WT or HER2 transgenic mice exhibited efficient ADCC of HER2-expressing tumor cells in vitro. Our findings define a critical requirement for NK cells in vaccine-induced protection against HER2-expressing tumors.
Triulzi
Chiara
C
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Vertuani
Simona
S
Curcio
Claudia
C
Antognoli
Agnese
A
Seibt
Josef
J
Akusjärvi
Göran
G
Wei
Wei-Zen
WZ
Cavallo
Federica
F
Kiessling
Rolf
R
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D017502:Adenovirus E2 Proteins / Q000235:genetics / Q000276:immunology; D000818:Animals; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011961:Receptors, Fc / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D015164:Vaccines, Inactivated / Q000235:genetics / Q000276:immunology
D017502:Adenovirus E2 Proteins; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D018719:Erb-b2 Receptor Tyrosine Kinases; D011961:Receptors, Fc; D015164:Vaccines, Inactivated