LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in HER-2/neu transgenic BALB/c mice.
Cancer Res
; 63(10): 2518-25, 2003 May 15.
Article
en En
| MEDLINE
| ID: mdl-12750275
Within 33 weeks of life, all 10 mammary glands of virgin BALB/c mice transgenic for the transforming rat HER-2/neu oncogene under the mammary tumor virus promoter (BALB-neuT mice) progress from atypical hyperplasia to invasive palpable carcinoma. Repeated DNA vaccination with plasmids coding for the extracellular and transmembrane domain of the protein product of rat HER-2/neu (r-p185(neu)) delayed tumor onset and reduced tumor multiplicity, but this protection eventually declined, and few mice were tumor free at 1 year of age. Association of plasmid vaccination with administration of soluble mouse LAG-3 (lymphocyte activation gene-3/CD223) generated by fusing the extracellular domain of murine LAG-3 to a murine IgG2a Fc portion (mLAG-3Ig) elicited a stronger and sustained protection that kept 70% of 1-year-old mice tumor free. Moreover, this combined vaccination, which was performed when multiple in situ carcinomas were already evident, extended disease-free survival and reduced carcinoma multiplicity. Inhibition of carcinogenesis was associated with markedly reduced epithelial cell proliferation and r-p185(neu) expression, whereas the few remaining hyperplastic foci were heavily infiltrated by reactive leukocytes. A stronger and enduring r-p185(neu)-specific cytotoxicity, a sustained release of IFN-gamma and interleukin 4, and a marked expansion of both CD8(+)/CD11b(+)/CD28(+) effector and CD8(+)/CD11b(+)/CD28(-) memory effector T-cell populations were induced in immunized mice. This combined vaccination also elicited a quicker and higher antibody response to r-p185(neu), as well as an early antibody isotype switch. These data suggest that the appropriate costimulation provided by mLAG-3Ig enables DNA vaccination to establish an effective protection, probably by enhancing cross-presentation of the DNA coded antigen.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Antígenos CD
/
Genes erbB-2
/
Vacunas contra el Cáncer
/
Vacunas de ADN
/
Neoplasias Mamarias Experimentales
/
Proteínas de la Membrana
Límite:
Animals
Idioma:
En
Revista:
Cancer Res
Año:
2003
Tipo del documento:
Article
País de afiliación:
Italia