Erbb2 DNA vaccine combined with regulatory T cell deletion enhances antibody response and reveals latent low-avidity T cells: potential and limits of its therapeutic efficacy.
Rat (r)Erbb2 transgenic BALB-neuT mice genetically predestined to develop multiple invasive carcinomas allow an assessment of the potential of a vaccine against the stages of cancer progression. Because of rErbb2 expression in the thymus and its overexpression in the mammary gland, CD8(+) T cell clones reacting at high avidity with dominant rErbb2 epitopes are deleted in these mice. In BALB-neuT mice with diffuse and invasive in situ lesions and almost palpable carcinomas, a temporary regulatory T cells depletion combined with anti-rErbb2 vaccine markedly enhanced the anti-rErbb2 Ab response and allowed the expansion of latent pools of low-avidity CD8(+) T cells bearing TCRs repertoire reacting with the rErbb2 dominant peptide. This combination of a higher Ab response and activation of a low-avidity cytotoxic response persistently blocked tumor progression at stages in which the vaccine alone was ineffective. However, when diffuse and invasive microscopic cancers become almost palpable, this combination was no longer able to secure a significant extension of mice survival.
Rolla
Simona
S
Molecular Biotechnology Center, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Ria
Francesco
F
Occhipinti
Sergio
S
Di Sante
Gabriele
G
Iezzi
Manuela
M
Spadaro
Michela
M
Nicolò
Chiara
C
Ambrosino
Elena
E
Merighi
Irene Fiore
IF
Musiani
Piero
P
Forni
Guido
G
Cavallo
Federica
F
D000818:Animals; D000906:Antibodies / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D002469:Cell Separation; D018274:Electroporation; D005260:Female; D005434:Flow Cytometry; D018734:Genes, erbB-2 / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology* / Q000494:pharmacology
D000906:Antibodies; D019496:Cancer Vaccines; D053645:Interleukin-2 Receptor alpha Subunit; D018719:Erb-b2 Receptor Tyrosine Kinases; D019444:Vaccines, DNA