Configuration-dependent Presentation of Multivalent IL-15:IL-15Rα Enhances the Antigen-specific T Cell Response and Anti-tumor Immunity

Abstract

It is well established that dendritic cells (DCs) 2 play a key role as professional antigen-presenting cells in initiating and coordinating antigen-specific adaptive immunity (1, 2). By constitutively sampling the external microenvironment through receptor-mediated and non-receptor mediated endocytic pathways, DCs initiate, program, and regulate the effector response against a variety of antigens (3-7). Although much is known about the immunobiology of DC antigen processing and presentation and the effect of different cytokines on DC maturation and their subsequent effect on the immune response (8), little is known about how the configuration or geometry of cytokine transmission affects the DC response. For example, physiologically, although IL-2 and IL-15 belong to the same four a-helix family of cytokines, IL-2 is transmitted as a soluble paracrine or autocrine factor (9, 10), whereas IL-15 is trans-presented on the surface of DCs and other cell types through a stable complex (11) with IL-15R␣ (12, 13) or secreted as a soluble paracrine complex (14, 15). The quality and manner by which cytokines are delivered to DCs can have a profound effect on the subsequent effector immune response (16,17).Nanosystems such as nanoparticles (18,19), nanotubes (20), or even macromolecular systems (21) comprise an emerging strategy for controlling antigen and cytokine transmission to . Perhaps one of the most explored carriers has been the polymeric poly(lactide-co-glycolide) (PLGA) system because of its significant promise and established effect in clinical settings (25-27) and well understood methods of formulation for delivery of small-molecule drugs, nucleic acids, and protein antigens (22, 28 -31). Several studies have demonstrated the promise of antigen-loaded PLGA nanoparticles as nanoparticle-based vaccines and delivery systems targeting DCs (32-39).IL-15 is a homeostatic cytokine for CD8 ϩ T cells and natural killer cells and an important regulator of the cytotoxic immune response (40). IL-15 signals by binding to cells expressing the IL-2/IL-15 ␤/␥ receptor and is found complexed to . This IL-15:IL-15R␣ complex is termed heterodimeric . IL-15R␣ is expressed by several cell types in * C. B. and G. N. P. are inventors on United States Government-owned patents and patent applications related to heterodimeric IL-15 and gene expression optimization. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Designing Multivalent Ligands to Control Biological Interactions: From Vaccines and Cellular Effectors to Targeted Drug Delivery

“…The quality and manner by which cytokines are delivered to DCs has been shown to have a profound influence on the resulting effector responses . Hong et al . designed antigen‐encapsulated nanoparticles multivalently presenting heterodimeric IL‐15 (hetIL‐15) on their surface.…”

“…The NP‐treated DCs showed enhanced stimulation of antigen specific CD8 + T cell responses and the localization of hetIL‐15 and antigen to the same DC led to greater responses compared to a soluble mixture of antigen and adjuvant. They also tested the impact of this configuration dependence in a murine melanoma model and demonstrated significantly delayed tumor progression in multivalent hetIL‐15 coated NPs in comparison to monovalent hetIL‐15 …”

“…[26] The quality and mannerb yw hich cytokines are delivered to DCs has been shown to have ap rofound influence on the resultinge ffector responses. [27,28] Hong et al [29] designed antigenencapsulated nanoparticles multivalently presenting heterodimeric IL-15 (hetIL-15) on their surface. The NP-treated DCs showede nhanced stimulation of antigen specific CD8 + Tc ell responses and the localizationo fh etIL-15 anda ntigen to the same DC led to greaterr esponses comparedt oasoluble mixture of antigen and adjuvant.…”

“…They also tested the impact of this configurationd ependence in am urinem elanoma model and demonstrated significantly delayed tumor progression in multivalent hetIL-15 coatedN Ps in comparison to monovalent hetIL-15. [29] The toll-like receptor (TLR) family is involved in the activation of many immune cells, including DCs. [30] Unmethylated cytosine-guanines (CpGs) derived from bacterial or viral genomes are specifically recognized by TLR9 on the surface of dendritic cells, Bc ells, and macrophages.…”

Nanomedicine in Melanoma: Current Trends and Future Perspectives

“…Another novel theranostic nanostructure for melanoma was a NP biodegradable photoluminescent polymer-poly (lactic acid) (BPLP-PLA) loaded with anti-BRAF V600E-specific drug (PLX4032) and muramyl peptide. The new immune-cell-mediated nanoparticle offers high hopes for melanoma imaging and treatment (121)(122)(123)(124)(125)(126).…”