Selective transduction of dendritic cells in human lymph nodes and superior induction of high-avidity melanoma-reactive cytotoxic t cells by a cd40-targeted adenovirus

Basav N. Hangalapura, Dinja Oosterhoff, Shikhar Aggarwal, Pepijn G.J.T.B. Wijnands, Rieneke Van De Ven, Saskia J.A.M. Santegoets, Monique Petrousjka Van Den Tol, Erik Hooijberg, Alexander Pereboev, Alfons J.M. Van Den Eertwegh, David T. Curiel, Rik J. Scheper, Tanja D. De Gruijl

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Targeted delivery of tumor antigen genes to dendritic cells (DCs) using adenoviral (Ad) vectors holds great potential for cancer immunotherapy. We previously showed that CD40 targeting of Ad vectors enhanced specific transduction of DC in human skin, while simultaneously ensuring their stable maturation and superior allogeneic T-cell stimulatory capacity. In this study, we evaluated whether CD40-targeted Ad encoding the full-length melanoma antigen recognized by T cells-1 (CD40-Ad-MART-1) could be used to efficiently and selectively transduce conventional and plasmacytoid DC to prime melanoma-specific CD8 T-effector cells in human melanoma-draining sentinel lymph nodes (SLNs). CD40 targeting of Ad was achieved using a bispecific fusion protein, binding and neutralizing the Ad fiber knob through soluble coxsackie and adenovirus receptor while retargeting the virus to hCD40 through the tumor necrosis factor-like domain of mCD40L. Selective transduction of conventional and plasmacytoid DC subsets by CD40-Ad was observed in suspensions of human melanoma-draining SLN. Moreover, CD40-Ad-MART-1 enhanced the expansion of functional MART-1-specific CD8 T cells from SLN with concomitant decreases in CD4:CD8 T-cell ratios and CD4CD25FoxP3 regulatory T-cell rates. Additional studies revealed that transduction and activation of monocyte-derived DCs with CD40-Ad-MART-1 significantly enhanced their priming efficiency of functional CD8 effector T cells with high avidity. These findings provide preclinical evidence of possible efficacy of this approach for cancer immunotherapy.

Original languageEnglish
Pages (from-to)706-715
Number of pages10
JournalJournal of Immunotherapy
Volume33
Issue number7
DOIs
StatePublished - Sep 1 2010
Externally publishedYes

Keywords

  • CD40
  • CTL
  • DC
  • adenovirus
  • melanoma

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    Hangalapura, B. N., Oosterhoff, D., Aggarwal, S., Wijnands, P. G. J. T. B., Van De Ven, R., Santegoets, S. J. A. M., Van Den Tol, M. P., Hooijberg, E., Pereboev, A., Van Den Eertwegh, A. J. M., Curiel, D. T., Scheper, R. J., & De Gruijl, T. D. (2010). Selective transduction of dendritic cells in human lymph nodes and superior induction of high-avidity melanoma-reactive cytotoxic t cells by a cd40-targeted adenovirus. Journal of Immunotherapy, 33(7), 706-715. https://doi.org/10.1097/CJI.0b013e3181eccbd4