Toll-like receptor 3 agonist complexed with cationic liposome augments vaccine-elicited antitumor immunity by enhancing TLR3–IRF3 signaling and type I interferons in dendritic cells

Wang, Ce; Zhuang, Yan; Zhang, Yijuan; Luo, Zichao; Gao, Ningning; Li, Ping; Pan, Hong; Cai, Lintao; Ma, Yifan

doi:10.1016/j.vaccine.2012.05.027

Cited by 63 publications

(46 citation statements)

References 38 publications

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“…Total protein was extracted from TADCs or splenocytes as previously reported [19]. Equal amount of cell lysates were separated by 10% SDS-PAGE gel and transferred onto a nitrocellulose membrane.…”

Section: Western Blotting Analysismentioning

confidence: 99%

“…Nanoparticles-based vaccine formulations not only facilitated antigen uptake by DCs, but also promoted DC maturation and antigen presentation [15,16], thereby enhancing anti-tumor immune responses [17,18]. Moreover, the encapsulation of nanoparticles was able to enhance the immunopotency of TLR agonists, such as monophosphoryl lipid A (MPLA, a TLR4 agonist) and Poly I: C (PIC, a TLR3 agonist), thereby further augmenting immunogenicity of vaccines [19,20]. We previously reported self-assembled cationic micelles based on poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-leucine) (PEG-PLL-PLLeu) hybrid polypeptides as a versatile and efficient delivery system for both genes and vaccines [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo

et al. 2015

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Section: Western Blotting Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo

et al. 2015

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“…The above results suggest that protection from LACV infection is dependent on IFN production by mDCs and that young mice are unable to generate this response. To determine if we could induce protection in young mice, we treated mice with cationic liposomes containing PRR agonists, which were previously shown to stimulate dendritic cells (32). Greater than 50% of the CD11c ϩ PDCA1 Ϫ mDCs took up fluorescently labeled liposomes (Fig.…”

Section: Irf3mentioning

confidence: 99%

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

Taylor

Woods

Winkler

et al. 2014

J Virol

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La Crosse virus (LACV) is the major cause of pediatric viral encephalitis in the United States; however, the mechanisms responsible for age-related susceptibility in the pediatric population are not well understood. Our current studies in a mouse model of LACV infection indicated that differences in myeloid dendritic cell (mDC) responses between weanling and adult mice accounted for susceptibility to LACV-induced neurological disease. We found that type I interferon (IFN) responses were significantly stronger in adult than in weanling mice. Production of these IFNs required both endosomal Toll-like receptors (TLRs) and cytoplasmic RIG-I-like receptors (RLRs). Surprisingly, IFN expression was not dependent on plasmacytoid DCs (pDCs) but rather was dependent on mDCs, which were found in greater number and induced stronger IFN responses in adults than in weanlings. Inhibition of these IFN responses in adults resulted in susceptibility to LACV-induced neurological disease, whereas postinfection treatment with type I IFN provided protection in young mice. These studies provide a definitive mechanism for age-related susceptibility to LACV encephalitis, where mDCs in young mice are insufficiently activated to control peripheral virus replication, thereby allowing virus to persist and eventually cause central nervous system (CNS) disease. IMPORTANCE La Crosse virus (LACV) is the primary cause of pediatric viral encephalitis in the UnitedStates. Although the virus infects both adults and children, over 80% of the reported neurological disease cases are in children. To understand why LACV causes neurological disease primarily in young animals, we used a mouse model where weanling mice, but not adult mice, develop neurological disease following virus infection. We found that an early immune response cell type, myeloid dendritic cells, was critical for protection in adult animals and that these cells were reduced in young animals. Activation of these cells during virus infection or after treatment with type I interferon in young animals provided protection from LACV. Thus, this study demonstrates a reason for susceptibility to LACV infection in young animals and shows that early therapeutic treatment in young animals can prevent neurological disease.

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“…Tumor-specific CTL response was conducted as previously described (24). For vaccine-induced T cell proliferation, total splenocytes were prelabeled with CFSE (Invitrogen, Carlsbad, CA), followed by incubation with 50 mg/ml OVA at 37˚C for 72 h. At the end of experiment, the splenocytes were harvested and labeled with PE anti-mouse CD4 or PE anti-mouse CD8 to identify CD4 + and CD8 + cells, respectively.…”

Section: In Vivo Experimentsmentioning

confidence: 99%

Integrated Nanovaccine with MicroRNA-148a Inhibition Reprograms Tumor-Associated Dendritic Cells by Modulating miR-148a/DNMT1/SOCS1 Axis

Liu

et al. 2016

The Journal of Immunology

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Immunosuppressive tumor-associated dendritic cells (TADCs) are potential targets for cancer therapy. However, their poor responsiveness to TLR stimulation is a major obstacle for achieving successful cancer immunotherapy. In the current study, we reported a dysregulated miR-148a/DNA methyltransferase (DNMT)1/suppressor of cytokine signaling (SOCS)1 axis as a unique mechanism for dampened TLR stimulation in TADCs. The results showed that aberrantly elevated miR-148a in bone marrow–derived TADC (BM-TADC) abolished polyinosinic-polycytidylic acid (poly I:C) or LPS-induced dendritic cell maturation through directly suppressing DNMT1 gene, which consequently led to the hypomethylation and upregulation of SOCS1, the suppressor of TLR signaling. In contrast, miR-148a inhibitor (miR-148ai) effectively rescued the expression of DNMT1 and decreased SOCS1 in BM-TADCs, thereby recovering their sensitivity to TLR3 or TLR4 stimulation. To further reprogram TADCs in vivo, miR-148ai was coencapsulated with poly I:C and OVA by cationic polypeptide micelles to generate integrated polypeptide micelle/poly I:C (PMP)/OVA/148ai nanovaccine, which was designed to simultaneously inhibit miR-148a and activate TLR3 signaling in TADCs. The immunization of PMP/OVA/148ai nanovaccine not only effectively modulated the miR-148a/DNMT1/SOCS1 axis in the spleen, but also significantly increased mature dendritic cells both in the spleen and in tumor microenvironment. Moreover, PMP/OVA/148ai ameliorated tumor immunosuppression through reducing regulatory T cells and myeloid-derived suppressor cells, thereby leading to potent anticancer immune responses and robust tumor regression with prolonged survival. This study proposes a nanovaccine-based immunogene therapy with the integration of miR-148a inhibition and TLR3 stimulation as a novel therapeutic approach to boost anticancer immunity by reprogramming TADCs in vivo.

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Toll-like receptor 3 agonist complexed with cationic liposome augments vaccine-elicited antitumor immunity by enhancing TLR3–IRF3 signaling and type I interferons in dendritic cells

Cited by 63 publications

References 38 publications

Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo

Nanovaccine loaded with poly I:C and STAT3 siRNA robustly elicits anti-tumor immune responses through modulating tumor-associated dendritic cells in vivo

Age-Dependent Myeloid Dendritic Cell Responses Mediate Resistance to La Crosse Virus-Induced Neurological Disease

Integrated Nanovaccine with MicroRNA-148a Inhibition Reprograms Tumor-Associated Dendritic Cells by Modulating miR-148a/DNMT1/SOCS1 Axis

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