Lymphocytes genetically modified to express tumor antigens target DCs in vivo and induce antitumor immunity

The exploitation of the physiologic processing and presenting machinery of DCs by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. Here we show that lymphocytes genetically modified to express self/tumor antigens, a...

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Vydané v:	The Journal of clinical investigation Ročník 117; číslo 10; s. 3087 - 3096
Hlavní autori:	Russo, Vincenzo, Cipponi, Arcadi, Raccosta, Laura, Rainelli, Cristina, Fontana, Raffaella, Maggioni, Daniela, Lunghi, Francesca, Mukenge, Sylvain, Ciceri, Fabio, Bregni, Marco, Bordignon, Claudio, Traversari, Catia
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States American Society for Clinical Investigation 01.10.2007
Predmet:	Animals Antigen Presentation Antigen-Presenting Cells - immunology Antigens Antigens, Neoplasm - genetics Apoptosis Autoantigens - genetics Biomedical research Bone marrow Cancer CD40 Antigens - immunology Cell Communication Cell Line, Tumor Cell Movement Dendritic cells Dendritic Cells - immunology Genetic aspects Growth factors Health aspects Immunotherapy Intramolecular Oxidoreductases - genetics Kinases Lymphocytes Melanoma Mice Mice, Transgenic Neoplasms - immunology Peptides Phagocytosis Proteins Stem cell transplantation T-Lymphocytes - immunology T-Lymphocytes - transplantation Tumor antigens Vaccines Italy
ISSN:	0021-9738, 1558-8238
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Shrnutí:	The exploitation of the physiologic processing and presenting machinery of DCs by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical efficacy of DC-based cancer vaccines. Here we show that lymphocytes genetically modified to express self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of tyrosinase-related protein 2-transduced (TRP-2-transduced) lymphocytes induced the establishment of protective immunity and long-term memory in tumor-bearing mice. Analysis of the mechanism responsible for the induction of such an immune response allowed us to demonstrate that cross-presentation of the antigen mediated by the CD11c(+)CD8alpha(+) DC subset had occurred. Furthermore, we demonstrated in vivo and in vitro that DCs had undergone activation upon phagocytosis of genetically modified lymphocytes, a process mediated by a cell-to-cell contact mechanism independent of CD40 triggering. Targeting and activation of secondary lymphoid organ-resident DCs endowed antigen-specific T cells with full effector functions, which ultimately increased tumor growth control and animal survival in a therapeutic tumor setting. We conclude that the use of transduced lymphocytes represents an efficient method for the in vivo loading of tumor-associated antigens on DCs.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0021-9738 1558-8238
DOI:	10.1172/JCI30605