Data di Pubblicazione:
2014
Abstract:
Purpose: Despite the great success of HER2 vaccine strategies in animal models, effective clinical results
have not yet been obtained. Westudied the feasibility of usingDNAcoding for chimeric rat/human HER2 as
a tool to break the unresponsiveness of T cells from patients with HER2-overexpressing tumors (HER2-CP).
Experimental Design: Dendritic cells (DCs) generated from patients with HER2-overexpressing breast
(n ¼ 28) and pancreatic (n ¼ 16) cancer were transfected with DNA plasmids that express human HER2 or
heterologous rat sequences in separate plasmids or as chimeric constructs encoding rat/human HER2 fusion
proteins and used to activate autologous T cells. Activation was evaluated by IFN-g ELISPOT assay, perforin
expression, and ability to halt HER2þ tumor growth in vivo.
Results: Specific sustained proliferation and IFN-g production by CD4 and CD8 T cells from HER2-CP
was observed after stimulation with autologous DCs transfected with chimeric rat/human HER2 plasmids.
Instead, T cells from healthy donors (n ¼ 22) could be easily stimulated with autologous DCs transfected
with any human, rat, or chimeric rat/human HER2 plasmid. Chimeric HER2-transfected DCs from HER2-
CP were also able to induce a sustained T-cell response that significantly hindered the in vivo growth of
HER2þ tumors. The efficacy of chimeric plasmids in overcoming tumor-induced T-cell dysfunction relies on
their ability to circumvent suppressor effects exerted by regulatory T cells (Treg) and/or interleukin (IL)-10
and TGF-b1.
Conclusions: These results provide the proof of concept that chimeric rat/human HER2 plasmids can be
used as effective vaccines for any HER2-CP with the advantage of being not limited to specific MHC.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
HER2; tolerance; DNA vaccine; Treg cells
Elenco autori:
Occhipinti S; Sponton L; Rolla S; Caorsi C; Novarino A; Donadio M; Bustreo S; Satolli MA; Pecchioni C; Marchini C; Amici A; Cavallo F; Cappello P; Pierobon D; Novelli F; Giovarelli M.
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