ABSTRACT
The growing enthusiasm for cancer immunotherapies and adoptive cell therapies has prompted increasing interest in biomaterials development mimicking natural antigen-presenting cells (APCs) for T-cell expansion. In contrast to conventional bottom-up approaches aimed at layering synthetic substrates with T-cell activation cues, transformation of live dendritic cells (DCs) into artificial APCs (aAPCs) is demonstrated herein using a facile and minimally disruptive hydrogelation technique. Through direct intracellular permeation of poly(ethylene glycol) diacrylate (PEG-DA) hydrogel monomer and UV-activated radical polymerization, intracellular hydrogelation is rapidly accomplished on DCs with minimal influence on cellular morphology and surface antigen display, yielding highly robust and modular cell-gel hybrid constructs amenable to peptide antigen exchange, storable by freezing and lyophilization, and functionalizable with cytokine-releasing carriers for T-cell modulation. The DC-derived aAPCs are shown to induce prolonged T-cell expansion and improve anticancer efficacy of adoptive T-cell therapy in mice compared to nonexpanded control T cells, and the gelation technique is further demonstrated to stabilize primary DCs derived from human donors. The work presents a versatile approach for generating a new class of cell-mimicking biomaterials and opens new venues for immunological interrogation and immunoengineering.
Subject(s)
Antigens/chemistry , Biocompatible Materials/chemistry , Biomimetic Materials/chemistry , Dendritic Cells/chemistry , Hydrogels/chemistry , Polyethylene Glycols/chemistry , Animals , Cell Membrane Permeability , Cell Proliferation , Cytokines/chemistry , Humans , Immunotherapy , Immunotherapy, Adoptive , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Neoplasms, Experimental , T-Lymphocytes , Ultraviolet RaysABSTRACT
The mucosal immune system is the host's first line of defense against invasion by foreign pathogens. Gelatin nanoparticles (GNPs) are suitable carriers for the delivery of antigens via various routes of administration. In the present study, GNPs were modified with polyethyleneimine (PEI), a positively charged polymer. Then, ovalbumin (OVA) and polyinosinic:polycytidylic acid (poly(I:C)), an immunostimulant, were adsorbed onto the surface of the positively charged GNPs. We assessed whether GNPs could act as an effective mucosal vaccine that is capable of inducing both mucosal and systemic immune responses. The results showed that GNPs effectively adsorbed OVA/poly(I:C), facilitated cellular uptake by RAW 264.7 macrophage cells and murine bone marrow-derived dendritic cells (BMDCs) in vitro, and led to increased expression of the maturation markers CD80 and CD86 on BMDCs. Furthermore, GNPs induced increased secretion of proinflammatory cytokines in both RAW 264.7 and BMDCs. C57BL/6 mice that were intranasally twice-immunized with OVA/poly(I:C)-loaded GNPs produced high levels of serum OVA-specific IgG antibodies and secretory IgA in nasal and lung lavage. Spleen cells from immunized mice were collected and re-stimulated with OVA, and results showed significantly augmented production of IFN-γ, IL-4, IL-5, and IL-6 in mice that received OVA/poly(I:C)-loaded GNPs. Moreover, intranasal immunization with OVA/poly(I:C)-loaded GNPs resulted in the inhibition of EG7 tumor growth in C57BL/6 mice. Taken together, these results indicate that nasal administration of OVA/poly(I:C)-loaded GNPs elicited effective mucosal and systemic immune responses, which might be useful for further applications of antigen delivery. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1228-1237, 2019.
