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A versatile supramolecular nanoadjuvant that activates NF-κB for cancer immunotherapy.

ABSTRACT: Although powerful adjuvants hold promise of vaccines for cancer immunotherapy, cumbersome preparation processes, elusive mechanisms and failure to induce T cell responses have largely limited their clinical translation. Due to their ease of synthesis, good biocompatibility and designable bioactivity, peptide derivatives-based supramolecular nanomaterials have attracted increasing interest in improving the immunogenicity of cancer vaccines. Methods: Herein, we synthesized an NF-κB-activating supramolecular nanoadjuvant (3DSNA) that is prepared by pH-triggering self-assembly of a positively charged D-configurational peptide derivative. The immunostimulatory activity of 3DNSA was explored in vitro and in vivo. Results: 3DSNA can strongly absorb the model antigen (ovalbumin, OVA) through electrostatic interaction. Then, 3DSNA promotes ingestion and cross-presentation of OVA, upregulation of costimulatory factors (CD80 and CD86) and secretion of proinflammatory cytokines (IL-6 and IL-12) by dendritic cells (DCs), accompanied by activation of the innate immune response (NF-κB signaling), resulting in long-term antigen-specific memory and effector CD8+ T cells response. When compared with conventional aluminum hydroxide adjuvant and the corresponding L-configurational supramolecular nanoadjuvant (3LSNA), 3DSNA-adjuvanted OVA (3DSNA+OVA) significantly prevents oncogenesis in naïve mice with a complete response rate of 60 %, restrains the tumor growth and prolongs the survival of melanoma-bearing mice. Conclusion: These findings demonstrate that 3DSNA is a promising neo-adjuvant that enables various vaccines to be therapeutic for many important diseases including cancer.

SUBMITTER: Xu Y

PROVIDER: S-EPMC6567969 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Anaplasma phagocytophilum subverts neutrophil function permitting intracellular survival, propagation and transmission. Sustained pro-inflammatory response, recruitment of new host cells for population expansion, and delayed apoptosis are associated with prolonged nuclear presence of NF-κB. We investigated NF-κB signaling and transcriptional activity with A. phagocytophilum infection using inhibitors of NF-κB signaling pathways, and through silencing of signaling pathway genes. How inhibitors or silencing affected A. phagocytophilum growth, inflammatory response (transcription of the κB-enhanced genes CXCL8 and MMP9), and NF-κB signaling pathway gene expression were tested. Among A. phagocytophilum-infected HL-60 cells, nuclear NF-κB p50, p65, and p52 were detected by immunoblots or iTRAQ proteomics. A. phagocytophilum growth was affected most by the IKKαβ inhibitor wedelolactone (reductions of 96 to 99%) as compared with SC-514 that selectively inhibits IKKβ, illustrating a role for the non-canonical pathway. Wedelolactone inhibited transcription of both CXCL8 (p = 0.001) and MMP9 (p = 0.002) in infected cells. Compared to uninfected THP-1 cells, A. phagocytophilum infection led to >2-fold down regulation of 64 of 92 NF-κB signaling pathway genes, and >2-fold increased expression in only 4. Wedelolactone and SC-514 reversed downregulation in all 64 and 45, respectively, of the genes down-regulated by infection, but decreased expression in 1 gene with SC-514 only. Silencing of 20 NF-κB signal pathway genes increased bacterial growth in 12 (IRAK1, MAP3K1, NFKB1B, MAP3K7, TICAM2, TLR3, TRADD, TRAF3, CHUK, IRAK2, LTBR, and MALT1). Most findings support canonical pathway activation; however, the presence of NFKB2 in infected cell nuclei, selective non-canonical pathway inhibitors that dampen CXCL8 and MMP9 transcription with infection, upregulation of non-canonical pathway target genes CCL13 and CCL19, enhanced bacterial growth with TRAF3 and LTBR silencing provide evidence for non-canonical pathway signaling. Whether this impacts distinct inflammatory processes that underlie disease, and whether and how A. phagocytophilum subverts NF-κB signaling via these pathways, need to be investigated.

Project description:BackgroundCheckpoint blockade therapies targeting programmed death ligand 1 (PD-L1) and its receptor programmed cell death 1 promote T cell-mediated immune surveillance against tumors and have been associated with significant clinical benefit in cancer patients. The long-stranded non-coding RNA HOTAIR is highly expressed and associated with metastasis in a variety of cancer types and promotes tumor metastasis at least in part through association with the PRC2 complex that induces redirection to hundreds of genes involved in tumor metastasis. Here, we report that HOTAIR is an activator lncRNA of the NF-κB pathway and demonstrate that its apparent upregulation promotes inflammatory signaling and immune escape in glioma cells.MethodsBioinformatics analysis was used to elucidate the relationship between HOTAIR and NF-κB pathway in HOTAIR knockdown glioma cells. At the cytological level, protein hybridization and immunofluorescence were used to detect the response of proteins in the NF-κB signaling pathway to HOTAIR regulation. ChIP and ChIRP experiments identified HOTAIR target genes. Animal experiments verified alterations in inflammation and immune escape following HOTAIR knockdown and activity inhibition.ResultsHOTAIR activated the expression of proteins involved in NF-κB, TNFα, MAPK and other inflammatory signaling pathways. In addition, HOTAIR induced various proteins containing protein kinase structural domains and promoted the enrichment of proteins and complexes of important inflammatory signaling pathways, such as the TNFα/NF-κB signaling protein complex, the IκB kinase complex, and the IKKA-IKKB complex. In addition, HOTAIR aberrantly activated biological processes involved in glioma immune responses, T-cell co-stimulation and transcription initiation by RNA polymerase II. HOTAIR facilitated the induction of IκBα phosphorylation by suppressing the expression of the NF-κB upstream protein UBXN1, promoting NF-κB phosphorylation and nuclear translocation. In vivo, reduction of HOTAIR decreased PD-L1 protein expression, indicating that cells are more likely to be targeted by immune T cells.ConclusionIn conclusion, our results provide convincing evidence that lncRNA HOTAIR drives aberrant gene transcription and immune escape from tumor cells through the NF-κB pathway.

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A versatile supramolecular nanoadjuvant that activates NF-κB for cancer immunotherapy.

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