Chirality of TLR-2 ligand Pam3CysSK4 in fully synthetic peptide conjugates critically influences the induction of specific CD8+ T-cells

Khan, Selina; Weterings, Jimmy J.; Britten, Cedrik M.; Jong, Ana R. de; Graafland, Dirk; Melief, Cornelis J.M.; Burg, Sjoerd H. van der; Marel, Gijs van der; Overkleeft, Hermen S.; Filippov, Dmitri V.; Ossendorp, Ferry

doi:10.1016/j.molimm.2008.10.006

Cited by 59 publications

(50 citation statements)

References 30 publications

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“…Likewise, coupling of minimal CTL epitopes to a synthetic TLR2-L has been reported to be an efficient vaccine modality (14). In agreement with these studies, we found that targeting of well-defined SLPs via TLRs is a highly potent method for optimal DC activation, efficient and sustained antigen presentation, and strong induction of specific CD8 þ T cells (15)(16)(17)(18). In our previous study, we have also examined the uptake and processing of the conjugated SLP in detail.…”

Section: Activation and Induction Of T-cell Immunity Rely On Antigen supporting

confidence: 78%

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Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Zom

Khan

Britten

et al. 2014

Cancer Immunology Research

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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 CD8þ 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 þ as well as CD8 þ T-cell responses and in vivo studies in two nonrelated aggressive tumor models. We show that TLR2-L SLP conjugates have superior mouse CD8 þ and CD4

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Section: Activation and Induction Of T-cell Immunity Rely On Antigen supporting

confidence: 78%

“…We have shown previously that synthetic TLR-L peptide conjugates containing a CTL epitope are efficiently targeted to DCs in vivo and are superior in inducing a strong CD8 þ T-cell immune response (15,16). In the present study, we report the effectiveness of the TLR2-L SLP conjugates in two aggressive tumor models.…”

Section: Discussionmentioning

confidence: 59%

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Zom

Khan

Britten

et al. 2014

Cancer Immunology Research

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“…27,41 Next to creating a beneficial milieu for inducing tumor-directed immunity, specific or enhanced targeting of TAAs to DCs has shown beneficial effects, for example by conjugating TAA to TLR ligands, 42 or generating antibody-antigen complexes. 43 These strategies may also be applied to apoptotic bleb-based vaccines.…”

Section: 1332mentioning

confidence: 99%

In situloading of skin dendritic cells with apoptotic bleb-derived antigens for the induction of tumor-directed immunity

et al. 2014

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The generation and loading of dendritic cells (DC) ex-vivo for tumor vaccination purposes is laborious and costly. Direct intradermal (i.d.) administration of tumor-associated antigens could be an attractive alternative approach, provided that efficient uptake and cross-presentation by appropriately activated skin DCs can be achieved. Here, we compare the efficiency of i.d. delivery of relatively small apoptotic blebs (diameter »0.1-1 mm) derived from MART-1 transduced acute myeloid leukemia (AML) HL60 cells, to that of larger apoptotic cell remnants (ACR; 2-10 mm) in a physiologically highly relevant human skin explant model. Injection of either fluorescently-labelled ACRs or blebs alone did not affect the number or distribution of migrated DC subsets from skin biopsies after 48 hours, but resulted in a general up-regulation of the co-stimulatory molecules CD83 and CD86 on skin DCs that had ingested apoptotic material. We have previously shown that i.d. administration of GM-CSF and IL-4 resulted in preferential migration of a mature and highly T cell-stimulatory CD11 hi CD1a C CD14 ¡ dermal DC subset. Here, we found that co-injection of GM-CSF and IL-4 together with either ACRs or blebs resulted in uptake efficiencies within this dermal DC subset of 7.6% ( §6.1%) and 19.1% ( §15.9%), respectively, thus revealing a significantly higher uptake frequency of blebs (P < 0.02). Intradermal delivery of tumor-derived blebs did not affect the T-cell priming and T H -skewing abilities of migratory skin DC. Nevertheless, in contrast to i.d. administration of ACR, the injection of blebs lead to effective cross-presentation of MART-1 to specific CD8 C effector T cells. We conclude that apoptotic bleb-based vaccines delivered through the skin may offer an attractive, and broadly applicable, cancer immunotherapy.

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“…Previously we have reported on the design, synthesis and immunological evaluation of constructs of TLR ligands covalently linked to a synthetic long peptide harboring a major histocompatibility complex (MHC) class I specific epitope [12]. Either the structurally defined TLR2-ligand Pam 3 CSK 4 [13–14], TLR7-ligand 7-hydroxy-8-oxoadenine [15] or TLR9-ligand CpG DNA [13] were covalently bound to a model antigen, an ovalbumin derived peptide comprising the MHC I epitope SIINFEKL, embedded in a longer peptide motif (DEVSGLEQLESIINFEKLAAAAAK, DEVA 5 K) [13,16]. We revealed that conjugates, in which Pam 3 CSK 4 or CpG DNA were incorporated, showed an increased uptake of conjugated peptide.…”

Section: Introductionmentioning

confidence: 99%

“…We revealed that conjugates, in which Pam 3 CSK 4 or CpG DNA were incorporated, showed an increased uptake of conjugated peptide. Increased DC maturation and enhanced antigen presentation was achieved in comparison to the mixture of the single peptide and ligands [13–14]. …”

Section: Introductionmentioning

confidence: 99%

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

Willems¹,

Zom²,

Meeuwenoord³

et al. 2014

Beilstein J. Org. Chem.

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SummaryThe covalent attachment of an innate immune system stimulating agent to an antigen can provide active vaccine modalities capable of eliciting a potent immune response against the incorporated antigen. Here we describe the design, automated synthesis and immunological evaluation of a set of four muramyl dipeptide–peptide antigen conjugates. Muramyl dipeptide (MDP) represents a well-known ligand for the intracellular NOD2 receptor and our study shows that covalently linking an MDP-moiety to an antigenic peptide can lead to a construct that is capable of stimulating the NOD2 receptor if the ligand is attached at the anomeric center of the muramic acid. The constructs can be processed by dendritic cells (DCs) and the conjugation does not adversely affect the presentation of the incorporated SIINFEKL epitope on MHC-I molecules. However, stimulation of the NOD2 receptor in DCs was not sufficient to provide a strong immunostimulatory signal.

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Chirality of TLR-2 ligand Pam3CysSK4 in fully synthetic peptide conjugates critically influences the induction of specific CD8+ T-cells

Cited by 59 publications

References 30 publications

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

In situloading of skin dendritic cells with apoptotic bleb-derived antigens for the induction of tumor-directed immunity

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

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