Self-adjuvanted nanovaccine for cancer immunotherapy: Role of lysosomal rupture-induced ROS in MHC class I antigen presentation
Introduction
Protein/peptide-based therapeutic cancer vaccines have emerged as a promising approach of cancer immunotherapy, which eradicates cancer cells by evoking anti-cancer immunity in patients [1]. For effective anti-cancer therapy, cancer vaccines should be able to trigger CD8+ T cell activation and anti-cancer cytotoxic T lymphocyte (CTL) responses, which require MHC class I (MHC I) antigen presentation by antigen-presenting cells, such as dendritic cells (DCs) and macrophages [1], [2]. To achieve optimal MHC I antigen presentation, protein/peptide antigens need to be degraded into small peptides, which primarily occurs in proteasomes, the multicatalytic protease complexes in the cytosol. Unfortunately, tumor-derived protein or peptide antigens are usually processed in the endo/lysosome compartment that generally favors MCH class II (MHC II) rather than MHC I antigen presentation [2], [3]. Hence, enhancing MHC class I antigen presentation of tumor antigens (so called “cross presentation”) is highly desirable to improve the anti-cancer efficacy of cancer vaccines.
Reactive oxygen species (ROS), as by-products of intracellular oxidative phosphorylation, participate in both innate and adaptive immune responses [4]. Previous studies have shown that laser- or H2O2-triggered ROS could act as a “danger” signal to promote DC maturation and enhance its ability to promote T cell proliferation [5]. More recent studies showed that ROS not only resulted in oxidized damages of intracellular proteins, but also enhanced the activation of proteasomes, thereby serving a key mechanism enhancing MHC I presentation in viral infected tissues [6], [7]. However, whether ROS is involved the cross presentation of soluble antigens in antigen-presenting cells remains unclear.
In the past decade, biodegradable nanoparticles have been reported as a potent vaccine delivery system to improve vaccine efficacy [8], [9]. For example, nanoparticle-based vaccine formulation can effectively increase antigen uptake by DCs through active and passive targeting [10], [11]. Nanoparticles can also directly stimulate DC maturation and activation, enhancing its antigen presenting capability [12], [13], [14]. More interestingly, biodegradable nanoparticles have been reported to effectively promote MHC class I/II antigen presentation [15]. We previously reported a bioreducible polysaccharide nanogel as potent vaccine adjuvant, which enhanced MHC I/II antigen presentation and anti-cancer CTL responses through facilitating lyososome escape and cytosolic release of tumor antigens in mouse DCs [16]. Liu Q et al. reported that pH-responsive nanoparticle enhanced rapid antigen release in lysosome and induced immune response [17]. Therefore, developing engineered biodegradable nanovectors for vaccine delivery holds a great potential for enhancing cross presentation and improving cancer vaccine efficacy.
Vitamin A, as an essential micronutrient, plays a crucial role in both innate and adaptive immunity, such as B cell and DC differentiation, CD4+ and CD8+ effector T cell activation, as well as tissue-specific lymphocyte homing [18], [19], [20]. The administration of vitamin A or its active metabolite, retinoic acid (RA), significantly enhances antigen-specific antibody production, CD8+ effector T cell activation and mucosal immunity [20], [21], indicating its potency as a vaccine adjuvant. The immunoregulatory effect of vitamin A is primarily mediated by DCs, in which vitamin A (retinol) can be sequentially oxidized to an active metabolite, all-trans retinoic acid (ATRA), and exert its biological function through binding to nuclear receptors retinoic acid receptor (RAR) and retinoic X receptor (RXR) [22]. In the present study, dextran was conjugated with all-trans retinal, a metabolite of vitamin A and an ATRA precusor, through a hydrazone bond, followed by galactosylation to obtain amphiphilic pH-sensitive galactosyl dextran-retinal (GDR) conjugates. Upon dissolved in water, GDR conjugates spontaneously self-assembled into pH-sensitive nanogel, which effectively encapsulated OVA antigen to form GDR/OVA nanovaccine. Since DCs are the most potent antigen present cells for initiating anti-cancer immune response, we used mouse bone marrow-derived dendritic cells (BMDCs) as a cell model to evaluate the effect of GDR on DC maturation, antigen uptake, and MHC I/II antigen presentation in vitro. The anti-cancer effect of GDR/OVA nanovaccine was further evaluated in tumor-bearing mouse model. Our results showed that GDR nanogel acted as a self-adjuvanted nanocarrier robustly augmenting vaccine-induced anti-cancer immune responses.
Section snippets
Materials
Dextran from Leuconostoc spp. (MW = 40,000), all-trans retinal, BMS493 (an inverse pan-RAR agonist), Ovalbumin (OVA, grade V), d-(+)-galactose were purchased from Sigma (MI, USA). Dimethylsulfoxide (DMSO) and 4-Nitrophenyl chloroformate (PNC) were purchased from J&K Scientific Ltd (Beijing, China). Lactobionic acid (LA),Ethylenediamine,1,1^′- carboxyl diimidazole (CDI), N-(3-Dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC), N- Hydroxysuccinimide (NHS), 4-(dimethylamino) pyridine
Preparation and characterization of GDR nanogel and GDR nanovaccine
Amphiphilic pH-sensitive galactosyl-dextran-retinal (GDR) conjugates were synthesized as shown in Supplementary Fig. S1. All-trans retinal, the precursor of RA, was first grafted to dextran through pH-sensitive hydrazone bond to generate amphiphilic dextran-retinal conjugate. In brief, dextran was activated by PNC to obtain DEX-PNC, followed by reaction with hydrazine hydrate to generate DEX–NH–NH2. DR conjugates were then obtained by the coupling reaction of DEX–NH–NH2 and all-trans retinal.
Conclusion
Enhancing antigen cross presentation by MHC I molecules is an important strategy to boost CD8+ CTL response and improve cancer vaccine efficacy. The present study reported amphiphilic pH-sensitive GDR nanogel as a self-adjuvanted vaccine delivery system, which not only promoted DC maturation and antigen uptake, but also triggered lysosomal rupture to facilitate cytosolic antigen release, thereby robustly enhancing MHC I antigen cross presentation and anti-cancer immunity. More interestingly, we
Acknowledgment
This work was supported by the National Natural Science Foundation of China (Grant No. 81171446, 81371679), Shenzhen Overseas Outstanding Professional Talent (KQCX201405201541150), Shenzhen Science and Technology Program (GJHS20140610151856702, CXZZ20130506140505859), Guangdong leading talents program (Antibody/Protein Drugs for Major Diseases), Shenzhen Peacock Next-generation Monoclonal Antibody Drug research and development program (KQTD201210).
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These authors equally contributed to this paper.