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Toll-like receptor agonists shape the immune responses to a mannose receptor-targeted cancer vaccine

Cellular & Molecular Immunology 2015年第6期12卷 719-728页

作者： Li-Zhen He Jeffrey Weidlick Crystal Sisson Henry C Marsh Tibor Keler Celldex Therapeutics Inc. Hampton N J USA and Celldex Therapeutics Inc. Needham MA USA

Previous studies have documented that selective delivery of protein antigens to cells expressing mannose receptor （MR） can lead to enhanced immune responses. We postulated that agents that influenced the MR expression level, and the activation and migration status of MR-expressing antigen presenting cells, would modulate immune responses to MR-targeted vaccines. To address this question, we investigated the effect of clinically used adjuvants in human MR transgenic （hMR-Tg） mice immunized with an MR-targeting cancer vaccine composed of the human anti-MR monoclonal antibody B 11 fused with the oncofetal protein, human chorionic gonadotropin beta chain （hCGβ）, and referred to as B 11-hCGβ. We found that humoral responses to low doses of B11-hCGβ could be enhanced by prior administration of GM-CSF, which upregulated MR expression in vivo. However, co-administration of the Toll-like receptor （TLR） agonists, poly-ICLC and/or CpG with B11-hCGβ was required to elicit Thl immunity, as measured by antigen-specific T-cell production of IFN-γ. The TLR agonists were shown to increase the number of vaccine-containing cells in the draining lymph nodes of immunized hMR-Tg mice. In particular, with B11-hCGβand poly-ICLC, a dramatic increase in vaccine-positive cells was observed in the T-ceU areas of the lymph nodes, compared to the vaccine alone or combined with GM-CSF. Importantly, the absence of the TLR agonists during the priming immunization led to antigen-specific tolerance. Therefore, this study provides insight into the mechanisms by which adjuvants can augment immune responses to B11-hCGβ and have implications for the rationale design of clinical studies combining MR-targeted vaccination with TLR agonists.

关键词： GM-CSF hCGβ mannose receptor Toll-like receptor agonists

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An antigen self-assembled and dendritic cell-targeted nanovaccine for enhanced immunity against cancer

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3518-3534页

作者： Yunting Zhang Min Jiangy Guangsheng Du Xiaofang Zhong Chunting He Ming Qin Yingying Hou Rong Liu Xun Sun Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

The rise of nanotechnology has opened new horizons for cancer ***,most nano vaccines fabricated with nanomaterials suffer from carrier-related concerns,including low drug loading capacity,unpredictable metabolism,and potential systemic toxicity,which bring obstacles for their clinical ***,we developed an antigen self-assembled nanovaccine,which was resulted from a simple acryloyl modification of the antigen to induce ***,a dendritic cell targeting head mannose monomer and a mevalonate pathway inhibitor zoledronic acid(Zol)were integrated or absorbed onto the nanoparticles(denoted as MEAO-Z)to intensify the immune *** synthesized nano vaccine with a diameter of around 70 nm showed successful lymph node transportation,high dendritic cell internalization,promoted costimulatory molecule expression,and preferable antigen *** virtue of the above superiorities,MEAO-Z induced remarkably higher titers of serum antibody,stronger cytotoxic T lymphocyte immune responses and IFN-γsecretion than free antigen and *** vivo,MEAO-Z significantly suppressed EG7-OVA tumor groth and prolonged the survival time of tumor-bearing *** results indicated the translation promise of our self-assembled nano vaccine for immune potentiation and cancer immunotherapy.

关键词： Subunit antigen Self-assembled nanovaccine Dendritic cell mannose receptor Zoledronic acid Antigen cross-presentation Cellular immunity Cancer immunotherapy

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Recognition of HBV antigens and HBV DNA by dendritic cells

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Hepatobiliary & Pancreatic Diseases International 2010年第6期9卷 584-592页

作者： Cui, Guang-Ying Diao, Hong-Yan Zhejiang Univ Sch Med Affiliated Hosp 1 State Key Lab Diag & Treatment Infect Dis Hangzhou 310003 Zhejiang Peoples R China

BACKGROUND: Hepatitis B virus (HBV) is a hepatotropic, noncytopathic, DNA virus which can cause acute and chronic infection. Viral persistence is associated with a weak or absent specific immune responses to HBV, particularly the cellular immune response. Dendritic cells (DCs) are professional antigen-presenting cells with a unique T cell stimulatory aptitude that play a crucial role in the instruction of adaptive immune responses upon infection. An impaired function of DCs was suggested by recent studies to account for the T and B cell hyporesponsiveness in chronic HBV infection. This review summarizes recent insights into the recognition of HBV antigens by DCs. DATA SOURCES: Studies were identified by searching MEDLINE and/or PubMed for articles using the key words 'hepatitis B virus (HBV)', 'dendritic cells', 'C-type lectins', 'mannose receptor', 'toll-like receptor', and 'dendritic cell-specific intercellular-adhesion-molecule-3 grabbing nonintegrin (DC-SIGN)' up to December 2009. Additional papers were identified by a manual search of the references from the key articles. RESULTS: DCs play an important role in the progress of hepatitis B, especially in the recognition of HBV. There are three main ways of recognition of HBV antigens by DCs. First, HBV DNA can be recognized by DCs through toll-like receptor 9 (TLR9) which activates the NF-kappa B signal pathway and p38 MAPK to up-regulate the expression of interferon (IFN) regulatory factor 7 (IRF-7) in a manner independent of type I IFN signaling, resulting in secretion of type I IFN and inflammatory cytokines, and induction of DC maturation and the adaptive immune response. Second, HBc/HBeAg cannot be recognized by DCs, but DNA or ssRNA encapsulated within HBcAg can be internalized by DCs through TLRs. Third, HBsAg can be internalized by DCs through the mannose receptor, which lacks the ability to induce DC maturation without the assistance of DC-SIGN. Meanwhile, there is some cross-talk among the three mechani

关键词： dendritic cells hepatitis B virus antigen HBV DNA toll-like receptor mannose receptor

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