Abstract
Langerhans cells (LCs) are antigen-presenting cells that reside in the skin. They uniquely express high levels of the C-type lectin receptor Langerin (CD207), which is an attractive target for antigen delivery in immunotherapeutic vaccination strategies against cancer. We here assess a library of 20 synthetic, well-defined mannoside clusters, built up from one, two, and three of six monomannosides, dimannosides, or trimannosides, appended to an oligopeptide backbone, for binding with Langerin using surface plasmon resonance and flow cytometric quantification. It is found that Langerin binding affinity increases with increasing number of mannosides. Hexavalent presentation of the mannosides resulted in binding affinities ranging from 3 to 12 μM. Trivalent presentation of the dimannosides and trimannosides led to Langerin affinity in the same range. The model melanoma gp100 antigenic peptide was subsequently equipped with a hexavalent cluster of the dimannosides and trimannosides as targeting moieties. Surprisingly, although the bifunctional conjugates were taken up in LCs in a Langerin-dependent manner, limited antigen presentation to cytotoxic T cells was observed. These results indicate that targeting glycan moieties on immunotherapeutic vaccines should not only be validated for target binding, but also on the continued effects on biology, such as antigen presentation to both CD8+ and CD4+ T cells.
Highlights
Immunotherapeutic vaccination is an appealing approach to direct the immune response toward specific tumor cells
In the direct interaction mode, where the Langerin extracellular domain (ECD) was bound to the sensor chip surface facing the ligands in the solvent, the apparent Kd was calculated for the ligands
In line with previous results, our study has shown an increase in affinity for the lectin with higher multivalent presentation of the mannoside saccharides
Summary
Immunotherapeutic vaccination is an appealing approach to direct the immune response toward specific tumor cells. Multiple antigen-presenting cell (APC) populations, including Langerhans cells (LCs), CD14+ dermal dendritic cells (dDCs), and CD1a+ dDCs, are present in the different layers of the skin, where they are key players in the activation of the adaptive immune response. The precise role and the antigen cross-presenting capacity of the different populations remains controversial. In this brief report, Langerin Targeting Bifunctional Mannosylated Antigens we set out to investigate LCs that reside in the epidermis. Langerhans cells play a key role in the induction of TH1 and TH17 responses by antigen-specific CD4+ T cells (Zaric et al, 2015). Depletion of LCs highly affected therapeutic epicutaneous immunization against cancer cells and reduced the protection by the immune system against tumor growth (Stoitzner et al, 2008)
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