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.
The demand is currently high for new vaccination strategies, particularly to help combat problematic intracellular pathogens, such as HIV and malarial parasites. In the past decade, the ...identification of host receptors that recognize pathogen-derived nucleic acids has revealed an essential role for nucleic acid sensing in the triggering of immunity to intracellular pathogens. This Review first addresses our current understanding of the nucleic acid-sensing immune machinery. We then explain how the study of nucleic acid-sensing mechanisms not only has revealed their central role in driving the responses mediated by many current vaccines, but is also revealing how they could be harnessed for the design of new vaccines.
Particulates such as silica crystal (silica) and aluminum salts (alum) activate the inflammasome and induce the secretion of proinflammatory cytokines in macrophages. These particulates also induce ...the production of immunoglobulin E via a T helper 2 (Th2) cell-associated mechanism. However, the mechanism involved in the induction of type 2 immunity has not been elucidated. Here, we showed that silica and alum induced lipopolysaccharide-primed macrophages to produce the lipid mediator prostaglandin E
2 (PGE
2) and interleukin-1β (IL-1β). Macrophages deficient in the inflammasome components caspase 1, NALP3, and ASC revealed that PGE
2 production was independent of the NALP3 inflammasome. PGE
2 expression was markedly reduced in PGE synthase-deficient (
Ptges
−/−) macrophages, and
Ptges
−/−mice displayed reduced antigen-specific serum IgE concentrations after immunization with alum or silica. Our results indicate that silica and alum regulate the production of PGE
2 and that the induction of PGE
2 by particulates controls the immune response in vivo.
► Silica and alum induced Mϕs to produce PGE
2 ► The inflammasome was not involved in silica- and alum-induced PGE
2 production ► Silica- and alum-induced PGE
2 regulate IgE production in vivo ► Lysosomal damage triggered PGE
2 production via the activation of Syk and p38
Spike protein mutation Leu455Ser is a hallmark mutation of JN.1: we have recently shown that HK.3 and other flip variants carry Leu455Phe, which contributes to increased transmissibility and immune ...escape ability compared with the parental EG.5.1 variant.5 Here, we investigated the virological properties of JN.1. KJI and KS are supported in part by AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers UTOPIA and by AMED SCARDA Program on R&D of new generation vaccine including new modality application. KS received funding from the AMED Research Program on HIV/AIDS, JST CREST, JSPS Core-to-Core Program, The Tokyo Biochemical Research Foundation, and The Mitsubishi Foundation; received consulting fees from Moderna Japan and Takeda Pharmaceutical; and honoraria for lectures from Gilead Sciences, Moderna Japan, and Shionogi & Co. JI received funding from JST PRESTO and JSPS KAKENHI Grant-in-Aid for Early-Career Scientists; and received consulting fees and honoraria for lectures from Takeda Pharmaceutical.
The recent success of cancer immunotherapies has highlighted the benefit of harnessing the immune system for cancer treatment. Vaccines have a long history of promoting immunity to pathogens and, ...consequently, vaccines targeting cancer neoantigens have been championed as a tool to direct and amplify immune responses against tumours while sparing healthy tissue. In recent years, extensive preclinical research and more than one hundred clinical trials have tested different strategies of neoantigen discovery and vaccine formulations. However, despite the enthusiasm for neoantigen vaccines, proof of unequivocal efficacy has remained beyond reach for the majority of clinical trials. In this Review, we focus on the key obstacles pertaining to vaccine design and tumour environment that remain to be overcome in order to unleash the true potential of neoantigen vaccines in cancer therapy.
Aluminum-based adjuvants (aluminum salts or alum) are widely used in human vaccination, although their mechanisms of action are poorly understood. Here we report that, in mice, alum causes cell death ...and the subsequent release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production after alum-adjuvanted immunization. We suggest that, on the one hand, host DNA induces primary B cell responses, including IgG1 production, through interferon response factor 3 (Irf3)-independent mechanisms. On the other hand, we suggest that host DNA also stimulates 'canonical' T helper type 2 (T(H)2) responses, associated with IgE isotype switching and peripheral effector responses, through Irf3-dependent mechanisms. The finding that host DNA released from dying cells acts as a damage-associated molecular pattern that mediates alum adjuvant activity may increase our understanding of the mechanisms of action of current vaccines and help in the design of new adjuvants.
The DNA damage response (DDR) induces the expression of type I interferons (IFNs), but the underlying mechanisms are poorly understood. Here, we show the presence of cytosolic DNA in different mouse ...and human tumor cells. Treatment of cells with genotoxic agents increased the levels of cytosolic DNA in a DDR-dependent manner. Cloning of cytosolic DNA molecules from mouse lymphoma cells suggests that cytosolic DNA is derived from unique genomic loci and has the potential to form non-B DNA structures, including R-loops. Overexpression of Rnaseh1, which resolves R-loops, reduced the levels of cytosolic DNA, type I Ifn transcripts, and type I IFN-dependent rejection of lymphoma cells. Live-cell imaging showed a dynamic contact of cytosolic DNA with mitochondria, an important organelle for innate immune recognition of cytosolic nucleotides. In summary, we found that cytosolic DNA is present in many tumor cells and contributes to the immunogenicity of tumor cells.
Double-stranded DNA (dsDNA) derived from pathogen- or host-damaged cells triggers innate immune responses when exposed to cytoplasm. However, the machinery underlying the primary recognition of ...intracellular dsDNA is obscure. Here we show that the DNA damage sensor, meiotic recombination 11 homolog A (MRE11), serves as a cytosolic sensor for dsDNA. Cells with a mutation of MRE11 gene derived from a patient with ataxia-telangiectasia–like disorder, and cells in which Mre11 was knocked down, had defects in dsDNA-induced type I IFN production. MRE11 physically interacted with dsDNA in the cytoplasm and was required for activation of stimulator of IFN genes (STING) and IRF3. RAD50, a binding protein to MRE11, was also required for dsDNA responses, whereas NBS1, another binding protein to MRE11, was dispensable. Collectively, our results suggest that the MRE11–RAD50 complex plays important roles in recognition of dsDNA and initiation of STING-dependent signaling, in addition to its role in DNA-damage responses.
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. Together, they make an effective type‐1 adjuvant and an anticancer agent. The synergistic effect between CpG ODN (K3) and STING‐ligand cyclic GMP–AMP (cGAMP), culminating in NK cell IFN‐γ (type‐II IFN) production, is due to the concurrent effects of IL‐12 and type‐I IFNs, which are differentially regulated by IRF3/7, STING, and MyD88. The combination of CpG ODN with cGAMP is a potent type‐1 adjuvant, capable of inducing strong Th1‐type responses, as demonstrated by enhanced antigen‐specific IgG2c and IFN‐γ production, as well as cytotoxic CD8+ T‐cell responses. In our murine tumor models, intratumoral injection of CpG ODN and cGAMP together reduced tumor size significantly compared with the singular treatments, acting as an antigen‐free anticancer agent. Thus, the combination of CpG ODN and a STING ligand may offer therapeutic application as a potent type‐II IFN inducer.
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