Abstract
Langerhans cells are a subset of dendritic cells residing in the epidermis of the human skin. As such, they are key mediators of immune regulation and have emerged as prime targets for novel transcutaneous cancer vaccines. Importantly, the induction of protective T cell immunity by these vaccines requires the efficient and specific delivery of both tumor-associated antigens and adjuvants. Langerhans cells uniquely express Langerin (CD207), an endocytic C-type lectin receptor. Here, we report the discovery of a specific, glycomimetic Langerin ligand employing a heparin-inspired design strategy and structural characterization by NMR spectroscopy and molecular docking. The conjugation of this glycomimetic to liposomes enabled the specific and efficient targeting of Langerhans cells in the human skin. We further demonstrate the doxorubicin-mediated killing of a Langerin+ monocyte cell line, highlighting its therapeutic and diagnostic potential in Langerhans cell histiocytosis, caused by the abnormal proliferation of Langerin+ myeloid progenitor cells. Overall, our delivery platform provides superior versatility over antibody-based approaches and novel modalities to overcome current limitations of dendritic cell-targeted immuno- and chemotherapy.
Highlights
The human skin is an attractive vaccination site due to the high density of immune cells compared to other organs such as the muscle.[1]
Human Langerhans cells (LCs) have been recognized for their capacity to internalize and cross-present exogenous antigens to elicit cytotoxic T cell responses, an established strategy for the development of novel cancer immunotherapies.[5,6]
Lesions in Langerhans cell histiocytosis (LCH) are predominantly composed of Langerin+ myeloid progenitor cells, and current treatments of this pediatric cancer would benefit from the targeted delivery of chemotherapeutics to reduce adverse effects.[26]
Summary
The human skin is an attractive vaccination site due to the high density of immune cells compared to other organs such as the muscle.[1]. As an alternative to epicutaneous administration, intradermal injection represents an attractive vaccination strategy for the skin.[25,62] the human dermis contains additional antigen-presenting cells including dermal DCs, macrophages, and monocytes These cells express a variety of GBPs such as MR, Dectin-1, DC-SIGN, and Siglec-10 and represent potential targets for glycomimetics.[63] In analogy to the experiments with epidermal skin cell suspensions, whole skin cell suspensions were utilized to analyze the specificity of the delivery platform in a physiologically relevant context (Figure 5).[60] Again, targeted liposomes were efficiently endocytosed by LCs. a minor population of CD1aintermediate-Langerin+ cells capable of internalizing liposomes was identified. Our findings demonstrate the specific cell killing and the efficient intracellular release of cargo upon Langerin-dependent endocytosis
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