LAG-3 enables DNA vaccination to persistently prevent mammary carcinogenesis in HER-2/neu transgenic BALB/c mice.
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.
Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy.
Paola
P
Cappello
Frederic
F
Triebel
Manuela
M
Iezzi
Cristiana
C
Caorsi
Elena
E
Quaglino
Pier-Luigi
PL
Lollini
Augusto
A
Amici
Emma
E
Di Carlo
Piero
P
Musiani
Mirella
M
Giovarelli
Guido
G
Forni
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D015703:Antigens, CD; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D018450:Disease Progression; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology*; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008565:Membrane Proteins / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019444:Vaccines, DNA / Q000276:immunology / Q000627:therapeutic use*; D000093322:Lymphocyte Activation Gene 3 Protein
D000276:Adjuvants, Immunologic; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D019496:Cancer Vaccines; D007074:Immunoglobulin G; D008565:Membrane Proteins; D019444:Vaccines, DNA; D000093322:Lymphocyte Activation Gene 3 Protein; C000720327:Lag3 protein, mouse