title: 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.
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 CD4(+)CD25(hi)FoxP3(+) 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.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Basav N
authors.initials: BN
authors.lastname: Hangalapura
authors.forename: Dinja
authors.initials: D
authors.lastname: Oosterhoff
authors.forename: Shikhar
authors.initials: S
authors.lastname: Aggarwal
authors.forename: Pepijn G J T B
authors.initials: PG
authors.lastname: Wijnands
authors.forename: Rieneke
authors.initials: R
authors.lastname: van de Ven
authors.forename: Saskia J A M
authors.initials: SJ
authors.lastname: Santegoets
authors.forename: Monique Petrousjka
authors.initials: MP
authors.lastname: van den Tol
authors.forename: Erik
authors.initials: E
authors.lastname: Hooijberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Pereboev
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D015704:CD4 Antigens / Q000096:biosynthesis; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D020014:K562 Cells; D008198:Lymph Nodes / Q000473:pathology; D058965:MART-1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic
chemical_list: D015704:CD4 Antigens; D019013:CD40 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D058965:MART-1 Antigen; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand; D007371:Interferon-gamma