Effects of N-acetyl-glucosamine-coated glycodendrimers as biological modulators in the B16F10 melanoma model in vivo.
Glyco-coat changes on cancer cells due to aberrant glycosylation are potential targets for immune recognition through lectin-like receptors on immune cells. These cells include natural killer (NK), CD8+ and CD4+ lymphocytes, all reported to have, together with cytokines, important functions in antitumor immunity. The aim of this study was to evaluate a possible role of synthetic monodisperse multivalent neo-glycoconjugates, namely glycodendrimers, as a new approach to anticancer immune modulation through carbohydrate-mediated immune recognition. Octavalent polyamidoamine dendrimers functionalized with N-acetyl-glucosamine residues (PAMAM-GlcNAc8), with in vitro high affinity for the recombinant lymphocyte receptor NKR-P1A, were employed. To follow the fate of the compound, a fluorescent marker was conjugated to the tetra-branched semi-component of the dendrimer. Tumor development and immunity were evaluated in C57BL/6 mice. Animals were inoculated with B16F10 melanoma cells and underwent different protocols of PAMAM-GlcNAc8 administration. Advantages on survival and reduction of tumor growth were obtained in dose-dependent manner, by IP route. Increase of CD69+ cells in the spleen and their appearance inside the tumors, early progressive release of IL-1beta, a later production of INFgamma and IL-2 concomitant to an increment of CD4+ cells were observed. Cytotoxicity assays, performed ex vivo, showed an enhanced NK cell activity proportioned to the percentage of activated NK cells. Our data suggest that well-defined multivalent neo-glycoconjugates can stimulate an antitumor immune response engaging both innate and acquired immunity.
Vannucci
Luca
L
Institute of Microbiology, Czech Academy of Sciences, 14220 Prague 4, Czech Republic. vannucci@biomed.cas.cz
Fiserová
Anna
A
Sadalapure
Kashinath
K
Lindhorst
Thisbe K
TK
Kuldová
Marketa
M
Rossmann
Pavel
P
Horváth
Ondrej
O
Kren
Vladimir
V
Krist
Pavel
P
Bezouska
Karel
K
Luptovcová
Martina
M
Mosca
Franco
F
Pospísil
Miloslav
M
D000117:Acetylglucosamine / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D001672:Biocompatible Materials; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D050091:Dendrimers; D004305:Dose-Response Relationship, Drug; D005456:Fluorescent Dyes; D006001:Glycoconjugates / Q000008:administration & dosage* / Q000737:chemistry; D007694:Killer Cells, Natural / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011073:Polyamines / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000954:Antigens, Surface; D001672:Biocompatible Materials; D016207:Cytokines; D050091:Dendrimers; D005456:Fluorescent Dyes; D006001:Glycoconjugates; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; C104700:PAMAM Starburst; D011073:Polyamines; D011994:Recombinant Proteins; D000117:Acetylglucosamine