Abstract
BackgroundDendritic cells (DC) pulsed with tumor-derived antigenic material have widely been used in antitumor vaccination protocols. However, the optimal strategy of DC loading has not yet been established. Our aim was to define requirements of optimal DC vaccines in terms of in vivo protection in a murine B-cell lymphoma model.MethodsWe compare various loading reagents including whole parental and modified tumor cells and a single tumor-specific antigen, namely the lymphoma idiotype (Id). Bone marrow-derived DC were pulsed in vitro and used for therapy of established A20 lymphomas.ResultsWe show that a vaccine with superior antitumor efficacy can be generated when DC are loaded with whole modified tumor cells which provide both (i) antigenic polyvalency and (ii) receptor-mediated antigen internalization. Uptake of cellular material was greatly enhanced when the tumor cells used for DC pulsing were engineered to express an anti-Fc receptor immunoglobulin specificity. Upon transfer of these DC, established tumor burdens were eradicated in 50% of mice. By contrast, pulsing DC with unmodified lymphoma cells or with the lymphoma Id, even when it was endowed with the anti-Fc receptor binding arm, was far less effective. A specific humoral anti-Id response could be detected, particularly following delivery of Id protein-pulsed DC, but it was not predictive of tumor protection. Instead a T-cell response was pivotal for successful tumor protection. Interaction of the transferred DC with CD8+ T lymphocytes seemed to play a role for induction of the immune response but was dispensable when DC had received an additional maturation stimulus.ConclusionOur analyses show that the advantages of specific antigen redirection and antigenic polyvalency can be combined to generate DC-based vaccines with superior antitumor efficacy. This mouse model may provide information for the standardization of DC-based vaccination protocols.
Highlights
Dendritic cells (DC) pulsed with tumor-derived antigenic material have widely been used in antitumor vaccination protocols
Our analyses show that the advantages of specific antigen redirection and antigenic polyvalency can be combined to generate DC-based vaccines with superior antitumor efficacy
Dendritic cells (DC) are professional antigen-presenting cells (APC) that are effective at presenting immunogenic peptides in the context of major histocompatibility complex (MHC) molecules and providing the costimulatory signals necessary for efficient T-cell stimulation [1,2,3]
Summary
Dendritic cells (DC) pulsed with tumor-derived antigenic material have widely been used in antitumor vaccination protocols. DC loaded with single TAA induced effective antitumor responses [5,8]. It was shown that loading of more than one epitope on APC inhibits T-cell priming [15] due to competition of peptides for MHC molecules and of T cells for access to APC. The consequences of this finding for antitumor immunization in vivo, have not yet been addressed and the optimal DC loading strategy still remains to be defined
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