Abstract
We have exploited the properties of filamentous bacteriophage fd to deliver immunologically active lipids together with antigenic peptides. Filamentous bacteriophages resemble for size, capability to be permeable to blood vessels, and high density antigen expression, a nature-made nanoparticle. In addition, their major coat protein pVIII, which is arranged to form a tubular shield surrounding the phage genome, has a high content of hydrophobic residues promoting lipid association. We conjugated bacteriophages to alpha-GalactosylCeramide (α-GalCer), a lipid antigen-stimulating invariant natural killer T (iNKT) cells and capable of inducing their anti-tumoral activities. We found that bacteriophage fd/α-GalCer conjugates could repeatedly stimulate iNKT cells in vitro and in vivo, without inducing iNKT anergy. Moreover, co-delivery of α-GalCer and a MHC class I restricted tumor-associated antigenic determinant to antigen-presenting cells via bacteriophages strongly boosted adaptive CD8+ T cell response and efficiently delayed tumor progression. Co-delivery of a tumor antigen and iNKT-stimulatory lipid on the surface of filamentous bacteriophages is a novel approach to potentiate adaptive anti-cancer immune responses, overcoming the current limitations in the use of free α-GalCer and may represent an attractive alternative to existing delivery methods, opening the path to a potential translational usage of this safe, inexpensive, and versatile tool.
Highlights
Invariant natural killer T cells represent a unique subpopulation of T lymphocytes with both innate-like and adaptive functions mainly found in spleen, liver, and bone marrow. invariant natural killer T (iNKT) cells express NK lineage receptors and a semi-invariant T cell receptor (TCR) composed of Vα14–Jα18 chain in mice and Vα24–Jα18 chain in humans, paired with β chains encoded by a limited number of Vβ genes [1]
The potential anti-tumoral function of iNKT cells was first discovered with the identification of alpha-GalactosylCeramide (α-GalCer), a synthetic derivative of agelasphin, a glycolipid origi nally isolated from the marine sponge Agelas mauritianus, as a strong stimulatory ligand during screening of anti-tumor compounds from natural sources [3,4,5]
To further improve the immune responses elicited by bacteriophage particles delivering antigenic peptides, in this work we exploited the capacity of the partially hydrophobic pVIII
Summary
In response to α-GalCer, iNKT cells rapidly secrete large quantities of cytokines, including IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-17, IL-21, IL-22, TGF-β, and TNF-α, that in turn activate a variety of other cell types, including NK cells, DCs, B, and T cells [6,7,8,9]. Through this activation cascade, α-GalCer showed to exert potent anti-tumor and adjuvant activities in vivo in mouse models [5, 10, 11], rendering it a powerful candidate for adjuvant therapy in cancer. Studies performed in a mouse model demonstrated that α-GalCer induced a long-term anergy of iNKT cells, preventing proliferation and cytokine release upon a recall stimulation [13]
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