title: Efficient induction of antitumor immunity by synthetic toll-like receptor ligand-peptide conjugates.
abstract: Chemical conjugates comprising synthetic Toll-like receptor ligands (TLR-L) covalently bound to antigenic synthetic long peptides (SLP) are attractive vaccine modalities, which can induce robust CD8(+) T-cell immune responses. Previously, we have shown that the mechanism underlying the power of TLR-L SLP conjugates is improved delivery of the antigen together with a dendritic cell activation signal. In the present study, we have expanded the approach to tumor-specific CD4(+) as well as CD8(+) T-cell responses and in vivo studies in two nonrelated aggressive tumor models. We show that TLR2-L SLP conjugates have superior mouse CD8(+) and CD4(+) T-cell priming capacity compared with free SLPs injected together with a free TLR2-L. Vaccination with TLR2-L SLP conjugates leads to efficient induction of antitumor immunity in mice challenged with aggressive transplantable melanoma or lymphoma. Our data indicate that TLR2-L SLP conjugates are suitable to promote integrated antigen-specific CD8(+) and CD4(+) T-cell responses required for the antitumor effects. Collectively, these data show that TLR2-L SLP conjugates are promising synthetic vaccine candidates for active immunotherapy against cancer.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre;
authors.forename: Gijs G
authors.initials: GG
authors.lastname: Zom
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre;
authors.forename: Selina
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre;
authors.forename: Cedrik M
authors.initials: CM
authors.lastname: Britten
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre;
authors.forename: Vinod
authors.initials: V
authors.lastname: Sommandas
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre;
authors.forename: Marcel G M
authors.initials: MG
authors.lastname: Camps
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre;
authors.forename: Nikki M
authors.initials: NM
authors.lastname: Loof
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre;
authors.forename: Christina F
authors.initials: CF
authors.lastname: Budden
authors.affiliation: Leiden Institute of Chemistry, Leiden University; and.
authors.forename: Nico J
authors.initials: NJ
authors.lastname: Meeuwenoord
authors.affiliation: Leiden Institute of Chemistry, Leiden University; and.
authors.forename: Dmitri V
authors.initials: DV
authors.lastname: Filippov
authors.affiliation: Leiden Institute of Chemistry, Leiden University; and.
authors.forename: Gijsbert A
authors.initials: GA
authors.lastname: van der Marel
authors.affiliation: Leiden Institute of Chemistry, Leiden University; and.
authors.forename: Hermen S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre; ISA Pharmaceuticals BV, Leiden, the Netherlands.
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre; f.a.ossendorp@lumc.nl.
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines; D002460:Cell Line; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D008024:Ligands; D055666:Lipopeptides / Q000276:immunology*; D008223:Lymphoma / Q000473:pathology / Q000628:therapy; D008546:Melanoma, Experimental / Q000473:pathology / Q000628:therapy; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000276:immunology*; D047368:Tumor Burden
chemical_list: D019496:Cancer Vaccines; D008024:Ligands; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2