Maturation of dendritic cells is a prerequisite for inducing immune responses in advanced melanoma patients.
OBJECTIVE
We have investigated the capacity of immature and mature monocyte-derived DCs pulsed with melanoma-associated peptides (gp100 and tyrosinase) to induce a primary cytotoxic T-lymphocyte response in vivo.


METHODS
Advanced HLA-A2.1(+) melanoma patients were vaccinated with peptide- and keyhole limpet hemocyanin (KLH)-pulsed DCs, either immature (9 patients) or matured by monocyte-conditioned medium/tumor necrosis factor alpha/prostaglandin E(2) (10 patients).


RESULTS
All patients vaccinated with mature DCs showed a pronounced proliferative T-cell and humoral response against KLH. By contrast, KLH responses were absent in most of the patients vaccinated with immature DCs. Delayed-type hypersensitivity (DTH) reactions against antigen-pulsed DCs were only observed in patients vaccinated with mature DCs and not in patients vaccinated with immature DCs. MHC-peptide tetramer staining of DTH-derived T cells revealed the presence of specific T cells recognizing the melanoma-associated peptides in 1 patient. In a second patient, DTH-derived T cells showed specific lysis of tumor cells expressing the antigens used for DC pulsing. Only patients vaccinated with mature DCs showed objective clinical responses. Interestingly, both patients with long-term progression-free survival (22 and >40 months) were both vaccinated with mature DCs and demonstrated antigen-specific T-cell reactivity of DTH-derived T cells.


CONCLUSIONS
We conclude that mature DC are superior to immature DC in the induction of immunological responses in melanoma patients, which may translate into improved clinical results.
de Vries
I Jolanda M
IJ
Department of Tumor Immunology,University Medical Center St. Radboud Nijmegen and Nijmegen Center for Molecular Life Sciences, Nijmegen, The Netherlands.
Lesterhuis
W Joost
WJ
Scharenborg
Nicole M
NM
Engelen
Linda P H
LP
Ruiter
Dirk J
DJ
Gerritsen
Marie-Jeanne P
MJ
Croockewit
Sandra
S
Britten
Cedrik M
CM
Torensma
Ruurd
R
Adema
Gosse J
GJ
Figdor
Carl G
CG
Punt
Cornelis J A
CJ
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002455:Cell Division; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D015789:HLA-A2 Antigen / Q000378:metabolism; D006433:Hemocyanins / Q000494:pharmacology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000556:secondary; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014611:Vaccination; D058951:gp100 Melanoma Antigen
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D058951:gp100 Melanoma Antigen; D007371:Interferon-gamma; D006433:Hemocyanins; D014442:Monophenol Monooxygenase; C032808:keyhole-limpet hemocyanin