期刊
CLINICAL CANCER RESEARCH
卷 20, 期 11, 页码 2910-2921出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-2663
关键词
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类别
资金
- Associazione Italiana per la Ricerca sul Cancro (AIRC IG) [9366, 5377, 11675, 12182, 5548, 11643]
- European Community, Seventh Framework Program European Pancreatic Cancer-Tumor-Microenvironment Network (EPC-TM-Net) [256974]
- Regione PIEMONTE: Ricerca Industriale Converging Technologies (BIOTHER), Progetti strategici su tematiche di interesse regionale o sovra regionale (IMMONC)
- Ministero dell'Istruzione e della Ricerca (MIUR), Progetti di Rilevante Interesse Nazionale (PRIN)
- University of Torino-Progetti di Ateneo : Mechanisms of REsistance to anti-angiogenesis regimens THErapy [Rethe-ORTO11RKTW]
- Fondazione Ricerca Molinette Onlus
- University of Torino
- Compagnia di San Paolo (Progetti di Ricerca Ateneo/CSP)
Purpose: Despite the great success of HER2 vaccine strategies in animal models, effective clinical results have not yet been obtained. We studied the feasibility of using DNA coding 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 = 28) and pancreatic (n 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-gamma ELISPOT assay, perforin expression, and ability to halt HER2+ tumor growth in vivo. Results: Specific sustained proliferation and IFN-gamma 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 = 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 HER2(+) 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-beta 1. 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. (C) 2014 AACR.
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