title: Local delivery of CpG-B and GM-CSF induces concerted activation of effector and regulatory T cells in the human melanoma sentinel lymph node.
abstract: Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. In an effort to determine the optimal way to strengthen immune defenses, 28 clinical stage I-II melanoma patients were randomized in a 3-arm Phase II study to receive, prior to excision and sampling of the SLN, i.d. injections of saline or low-dose CpG-B (CpG), alone or combined with GM-CSF (GM), around the melanoma excision site. We previously described the combined administration of these DC-targeting agents to result in activation and recruitment of potentially cross-presenting BDCA3(+) DCs to the SLN. In this report we describe the effects on effector and regulatory T and NK cell subsets. Local low-dose CpG administration resulted in lower CD4/CD8 ratios, Th1 skewing, increased frequencies of melanoma-specific CD8(+) T cells and possible recruitment of effector NK cells, irrespective of GM co-administration. These immune-potentiating effects were counterbalanced by increased IL-10 production by T cells and significantly higher levels of FoxP3 and CTLA4 in regulatory T cells (Tregs) with correspondingly higher suppressive activity in the SLN. Notably, CpG ± GM-administered patients showed significantly lower numbers of SLN metastases (saline: 4/9, CpG + GM: 1/9, CpG: 0/10, p = 0.04). These findings indicate that i.d. delivery of low-dose CpG ± GM potentially arms the SLN of early-stage melanoma patients against metastatic spread, but that antitumor efficacy may be further boosted by counteracting the collateral activation of Tregs.
authors.affiliation: Department of Pathology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Mari F C M
authors.initials: MF
authors.lastname: van den Hout
authors.affiliation: Department of Surgical Oncology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Berbel J R
authors.initials: BJ
authors.lastname: Sluijter
authors.affiliation: Department of Medical Oncology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, De Boelelaan 1117, Room CCA 2.44, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Saskia J A M
authors.initials: SJ
authors.lastname: Santegoets
authors.affiliation: Department of Surgical Oncology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Paul A M
authors.initials: PA
authors.lastname: van Leeuwen
authors.affiliation: Department of Surgical Oncology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: M Petrousjka
authors.initials: MP
authors.lastname: van den Tol
authors.affiliation: Department of Medical Oncology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, De Boelelaan 1117, Room CCA 2.44, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Alfons J M
authors.initials: AJ
authors.lastname: van den Eertwegh
authors.affiliation: Department of Pathology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
authors.forename: Rik J
authors.initials: RJ
authors.lastname: Scheper
authors.affiliation: Department of Medical Oncology, Cancer Center Amsterdam, Vrije Universiteit (VU) University Medical Center, De Boelelaan 1117, Room CCA 2.44, 1081 HV, Amsterdam, The Netherlands. td.degruijl@vumc.nl.
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016516:CD4-CD8 Ratio; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000627:therapeutic use*; D021701:Sentinel Lymph Node Biopsy; D016037:Single-Blind Method; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D009838:Oligodeoxyribonucleotides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: CpG; GM-CSF; Immunotherapy; Melanoma; Regulatory T cells; Sentinel lymph node