5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation.

5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown.

TLR9 plus STING Agonist Adjuvant Combination Induces Potent Neopeptide T Cell Immunity and Improves Immune Checkpoint Blockade Efficacy in a Tumor Model.

Immune checkpoint blockade (ICB) immunotherapies have emerged as promising strategies for the treatment of cancer; however, there remains a need to improve their efficacy. Determinants of ICB efficacy are the frequency of tumor mutations, the associated neoantigens, and the T cell response against them. Therefore, it is expected that neoantigen vaccinations that boost the antitumor T cell response would improve ICB therapy efficacy.

CpG ODN (K3)-toll-like receptor 9 agonist-induces Th1-type immune response and enhances cytotoxic activity in advanced lung cancer patients: a phase I study.

Background: Cytosine-phosphate-guanine oligodeoxynucleotide (CpG ODN) (K3)-a novel synthetic single-stranded DNA immune adjuvant for cancer immunotherapy-induces a potential Th1-type immune response against cancer cells. We conducted a phase I study of CpG ODN (K3) in patients with lung cancer to assess its safety and patients' immune responses.

Methods: The primary endpoint was the proportion of dose-limiting toxicities (DLTs) at each dose level.

Safety and immunogenicity of a quadrivalent seasonal influenza vaccine adjuvanted with hydroxypropyl-β-cyclodextrin: A phase 1 clinical trial.

Objectives: Hydroxypropyl-β-cyclodextrin (HP-β-CyD), an oligosaccharide used as an excipient in pharmaceutical preparation, was recently reported to function as a vaccine adjuvant to co-administered antigens. In this study, we investigated the safety and immunogenicity of a seasonal influenza vaccine adjuvanted with HP-β-CyD (FluCyD-vac) in healthy adults compared with those of a standard seasonal influenza vaccine (Flu-vac).

Methods: We conducted a single-blinded randomized phase 1 clinical trial study, and used two quadrivalent split seasonal influenza vaccines: FluCyD-vac containing 9 μg of HA/strain and 20% w/v of HP-β-CyD, and Flu-vac containing 15 μg of hemagglutinin (HA)/strain only.

Machine Learning-Assisted Screening of Herbal Medicine Extracts as Vaccine Adjuvants.

Adjuvants are important vaccine components, composed of a variety of chemical and biological materials that enhance the vaccine antigen-specific immune responses by stimulating the innate immune cells in both direct and indirect manners to produce a variety cytokines, chemokines, and growth factors. It has been developed by empirical methods for decades and considered difficult to choose a single screening method for an ideal vaccine adjuvant, due to their diverse biochemical characteristics, complex mechanisms of, and species specificity for their adjuvanticity. We therefore established a robust adjuvant screening strategy by combining multiparametric analysis of adjuvanticity and immunological profiles (such as cytokines, chemokines, and growth factor secretion) of various library compounds derived from hot-water extracts of herbal medicines, together with their diverse distribution of nano-sized physical particle properties with a machine learning algorithm.

Anti-tumor immunity by transcriptional synergy between TLR9 and STING activation.

Agonists for TLR9 and stimulator of IFN genes (STING) offer therapeutic applications as both anti-tumor agents and vaccine adjuvants, though their clinical applications are limited; the clinically available TLR9 agonist is a weak IFN inducer and STING agonists induce undesired type 2 immunity. Yet, combining TLR9 and STING agonists overcame these limitations by synergistically inducing innate and adaptive IFNγ to become an advantageous type 1 adjuvant, suppressing type 2 immunity, in addition to exerting robust anti-tumor activities when used as a monotherapeutic agent for cancer immunotherapy. Here, we sought to decipher the immunological mechanisms behind the synergism mediated by TLR9 and STING agonists and found that their potent anti-tumor immunity in a Pan02 peritoneal dissemination model of pancreatic cancer was achieved only when agonists for TLR9 and STING were administered locally, and was via mechanisms involving CD4 and CD8 T cells as well as the co-operative action of IL-12 and type I IFNs.

B cell-intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice.

The germinal center (GC) is a site where somatic hypermutation and clonal selection are coupled for antibody affinity maturation against infections. However, how GCs are formed and regulated is incompletely understood. Here, we identified an unexpected role of Tank-binding kinase-1 (TBK1) as a crucial B cell-intrinsic factor for GC formation.

Type I and II interferons toward ideal vaccine and immunotherapy.

: Innate immunity is armed with interferons (IFNs) that link innate immunity to adaptive immunity to generate long-term and protective immune responses against invading pathogens and tumors. However, regulation of IFN production is crucial because chronic IFN responses can have deleterious effects on both antitumor and antimicrobial immunity in addition to provoking autoinflammatory or autoimmune conditions.: Here, we focus on the accumulated evidence on antimicrobial and antitumor activities of type I and II IFNs.

Cyclic GMP-AMP Triggers Asthma in an IL-33-Dependent Manner That Is Blocked by Amlexanox, a TBK1 Inhibitor.

Extracellular host-derived DNA, as one of damage associated molecular patterns (DAMPs), is associated with allergic type 2 immune responses. Immune recognition of such DNA generates the second messenger cyclic GMP-AMP (cGAMP) and induces type-2 immune responses; however, its role in allergic diseases, such as asthma, has not been fully elucidated. This study aimed to determine whether cGAMP could induce asthma when used as an adjuvant.

B cell-intrinsic MyD88 signaling controls IFN-γ-mediated early IgG2c class switching in mice in response to a particulate adjuvant.

Adjuvants improve the potency of vaccines, but the modes of action (MOAs) of most adjuvants are largely unknown. TLR-dependent and -independent innate immune signaling through the adaptor molecule MyD88 has been shown to be pivotal to the effects of most adjuvants; however, MyD88's involvement in the TLR-independent MOAs of adjuvants is poorly understood. Here, using the T-dependent antigen NIPOVA and a unique particulate adjuvant called synthetic hemozoin (sHZ), we show that MyD88 is required for early GC formation and enhanced antibody class-switch recombination (CSR) in mice.

Inhaled Fine Particles Induce Alveolar Macrophage Death and Interleukin-1α Release to Promote Inducible Bronchus-Associated Lymphoid Tissue Formation.

Particulate pollution is thought to function as an adjuvant that can induce allergic responses. However, the exact cell types and immunological factors that initiate the lung-specific immune responses are unclear. We found that upon intratracheal instillation, particulates such as aluminum salts and silica killed alveolar macrophages (AMs), which then released interleukin-1α (IL-1α) and caused inducible bronchus-associated lymphoid tissue (iBALT) formation in the lung.

Circulating nano-particulate TLR9 agonist scouts out tumor microenvironment to release immunogenic dead tumor cells.

Recent evidence suggest that a β-glucan derived from mushroom Schizophyllan(SPG) complexed with a humanized TLR9 agonistic CpG DNA, K3 (K3-SPG) is a promising vaccine adjuvant that induces robust CD8 T cell responses to co-administered antigen. However, it has not been investigated whether K3-SPG alone can act as an anti-cancer immunotherapeutic agent or not. Here, we demonstrate that intravenous injection of K3-SPG, but not CpG alone, is accumulated in the tumor microenvironment and triggered immunogenic cell death (ICD) of tumor cells by local induction of type-I interferon (IFN) as well as IL-12.

Vaccine adjuvants as potential cancer immunotherapeutics.

Accumulated evidence obtained from various clinical trials and animal studies suggested that cancer vaccines need better adjuvants than those that are currently licensed, which include the most commonly used alum and incomplete Freund's adjuvant, because of either a lack of potent anti-tumor immunity or the induction of undesired immunity. Several clinical trials using immunostimulatory adjuvants, particularly agonistic as well as non-agonistic ligands for TLRs, C-type lectin receptors, retinoic acid-inducible gene I-like receptors and stimulator of interferon genes, have revealed their therapeutic potential not only as vaccine adjuvants but also as anti-tumor agents. Recently, combinations of such immunostimulatory or immunomodulatory adjuvants have shown superior efficacy over their singular use, suggesting that seeking optimal combinations of the currently available or well-characterized adjuvants may provide a better chance for the development of novel adjuvants for cancer immunotherapy.

Species-dependent role of type I IFNs and IL-12 in the CTL response induced by humanized CpG complexed with β-glucan.

CpG oligodeoxynucleotide (ODN) is one of promising nucleic acid-based adjuvants. We recently improved its ability to enhance CD8(+) T-cell responses to coadministered protein antigen without conjugation or emulsion, by forming a nanoparticulate complex between CpG ODN (K3) and mushroom-derived β-glucan schizophyllan (SPG), namely K3-SPG. Here, we sought to elucidate the cellular immunological mechanisms by which K3-SPG induce such potent CD8(+) T-cell responses to coadministered antigen.

TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN.

Agonists for TLR9 and Stimulator of IFN Gene (STING) act as vaccine adjuvants that induce type-1 immune responses. However, currently available CpG oligodeoxynucleotide (ODN) (K-type) induces IFNs only weakly and STING ligands rather induce type-2 immune responses, limiting their potential therapeutic applications. Here, we show a potent synergism between TLR9 and STING agonists.