title: Arming the Melanoma Sentinel Lymph Node through Local Administration of CpG-B and GM-CSF: Recruitment and Activation of BDCA3/CD141(+) Dendritic Cells and Enhanced Cross-Presentation.
abstract: Melanoma-induced suppression of dendritic cells (DC) in the sentinel lymph node (SLN) interferes with the generation of protective antitumor immunity. In an effort to strengthen immune defense against metastatic spread, we performed a three-arm phase II study comprising 28 patients with stage I-II melanoma randomized to receive intradermal injections around the primary tumor excision site of saline or low-dose CpG-B, alone or combined with GM-CSF, before excision of the SLNs. After pathologic examination, 5 patients were diagnosed with stage III melanoma based on the presence of tumor cells in the SLNs. Combined CpG/GM-CSF administration resulted in enhanced maturation of all identifiable conventional (cDC) and plasmacytoid (pDC) DC subsets and selectively induced increased frequencies of SLN-resident BDCA3/CD141(+) cDC subsets that also expressed the C-type lectin receptor CLEC9A. Correlative in vivo analyses and in vitro studies provided evidence that these subsets were derived from BDCA3(+) cDC precursors in the blood that were recruited to the SLNs in a type I IFN-dependent manner and subsequently matured under the combined influence of CpG and GM-CSF. In line with their reported functional abilities, frequencies of in vivo CpG/GM-CSF-induced BDCA3/CD141(+) DCs correlated with increased ex vivo cross-presenting capacity of SLN suspensions. Combined local CpG/GM-CSF delivery thus supports protective antimelanoma immunity through concerted activation of pDC and cDC subsets and recruitment of BDCA3(+) cDC subsets with T cell-stimulatory and cross-priming abilities.
authors: Department of Surgical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Berbel J R
authors: BJ
authors: Sluijter
authors: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Mari F C M
authors: MF
authors: van den Hout
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Bas D
authors: BD
authors: Koster
authors: Department of Surgical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Paul A M
authors: PA
authors: van Leeuwen
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Famke L
authors: FL
authors: Schneiders
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Rieneke
authors: R
authors: van de Ven
authors: Department of Surgical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Barbara G
authors: BG
authors: Molenkamp
authors: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Saskia
authors: S
authors: Vosslamber
authors: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Cornelis L
authors: CL
authors: Verweij
authors: Department of Surgical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors: M Petrousjka
authors: MP
authors: van den Tol
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Alfons J M
authors: AJ
authors: van den Eertwegh
authors: Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands.
authors: Rik J
authors: RJ
authors: Scheper
authors: Department of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands. td.degruijl@vumc.nl.
authors: Tanja D
authors: TD
authors: de Gruijl
mesh_terms: D000328:Adult; D000368:Aged; D000954:Antigens, Surface / Q000276:immunology; D002478:Cells, Cultured; D045142:Cross-Priming; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D008198:Lymph Nodes / Q000187:drug effects* / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology*; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D021701:Sentinel Lymph Node Biopsy; D018180:Thrombomodulin
chemical_list: D000954:Antigens, Surface; D016207:Cytokines; D009838:Oligodeoxyribonucleotides; C483020:ProMune; C546931:THBD protein, human; D018180:Thrombomodulin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor