Trailblazing in adjuvant research: succinate's uncharted territory with neutrophils.

The purpose of this study is to investigate the previously unknown connection that succinate has with neutrophils in the setting of adjuvant-mediated immunological enhancement. It has been discovered that succinates stimulate the recruitment of neutrophils in immunization sites, which in turn induces the expression of what is known as neutrophil-derived B cell-activating factor (BAFF). Further amplification of vaccine-induced antibody responses is provided via the succinate receptor 1-interferon regulatory factor 5 (SUCNR1-IRF5)-BAFF signaling pathway, which provides insights into a unique mechanism for immunological enhancement.NEW & NOTEWORTHY This study explores the role of succinate as a vaccine adjuvant, revealing its capacity to enhance neutrophil recruitment at immunization sites, which boosts B cell activation through the succinate receptor 1-interferon regulatory factor 5-B cell-activating factor (SUCNR1-IRF5-BAFF) signaling pathway. Results demonstrate succinate's potential to amplify vaccine-induced antibody responses, highlighting its significance in immunological enhancement and offering new insights into the adjuvant mechanisms of action, particularly in neutrophil-mediated immune responses.

Massively recruited sTLR9+ neutrophils in rapidly formed nodules at the site of tumor cell inoculation and their contribution to a pro-tumor microenvironment.

Neutrophils exert either pro- or anti-tumor activities. However, few studies have focused on neutrophils at the tumor initiation stage. In this study, we unexpectedly found a subcutaneous nodule in the groin areas of mice inoculated with tumor cells. The nodule was developed 24 h after the inoculation, filled with tumor cells and massively recruited neutrophils, being designated as tumor nodules. 22% of the neutrophils in tumor nodules are surface TLR9 (sTLR9) expressing neutrophils (sTLR9+ neutrophils). With tumor progression, sTLR9+ neutrophils were sustainably increased in tumor nodules/tumor tissues, reaching to 90.8% on day 13 after inoculation, with increased expression of IL-10 and decreased or no expression of TNFα. In vivo administration of CpG 5805 significantly reduced sTLR9 expression of the sTLR9+ neutrophils. The reduction of sTLR9 on neutrophils in tumor nodules contributed to the induction of an anti-tumor microenvironment conductive to the inhibition of tumor growth. Overall, the study provides insights for understanding the role of sTLR9+ neutrophils in the tumor development, especially in the early stage.

Immunotherapy for lung cancer combining the oligodeoxynucleotides of TLR9 agonist and TGF-ß2 inhibitor.

Tumor immunotherapies have shown promising antitumor effects, especially immune checkpoint inhibitors (ICIs). However, only 12.46% of the patients benefit from the ICIs, the rest of them shows limited effects on ICIs or even accelerates the tumor progression due to the lack of the immune cell infiltration and activation in the tumor microenvironment (TME). In this study, we administrated a combination of Toll-like receptor 9 (TLR9) agonist CpG ODN and Transforming growth factor-ß2 (TGF-ß2) antisense oligodeoxynucleotide TIO3 to mice intraperitoneally once every other day for a total of four injections, and the first injection was 24 h after LLC cell inoculation. We found that the combination induced the formation of TME toward the enrichment and activation of CD8+ T cells and NK cells, accompanied with a marked decrease of TGF-ß2. The combined therapy also effectively inhibited the tumor growth and prolonged the survival of the mice, even protected the tumor-free mice from the tumor re-challenge. Both of CpG ODN and TIO3 are indispensable, because replacing CpG ODN with TLR9 inhibitor CCT ODN showed no antitumor effect, CpG ODN or TIO3 alone did not lead to ideal antitumor results. This effect was possibly initiated by the activation of dendritic cells at the tumor site. This systemic antitumor immunotherapy with a combination of the two oligonucleotides (an immune stimulant and an immunosuppressive cytokine inhibitor) before the tumor formation may provide a novel strategy for clinical prevention of the postoperative tumor recurrence.

Prevalence and potential risk factors of PDCoV in pigs based on publications during 2015-2021 in China: Comprehensive literature review and meta-analysis.

Porcine deltacoronavirus (PDCoV), a novel coronavirus which infects pigs, spreading around the world and causing huge economic losses. In recent years, there have also been human cases of PDCoV infection, which poses a potential threat to public health. Therefore, we conducted a systematic review and meta-analysis to assess the prevalence of PDCoV in pigs in China between 2015 and 2021. The prevalence of PDCoV in China was searched from five databases (CNKI, VIP, WanFang, PubMed and ScienceDirect) and 65 articles met the inclusion criteria, with a total of 25,977 samples, including 3828 positive cases. The overall prevalence of PDCoV was 13.61% (3828/25,977), with the highest prevalence in northern China (19.18%) and the lowest prevalence in southwest China (7.19%). We also analyzed other subgroup information, such as sampling years, test methods, age and geographic factors. The results show that PDCoV is endemic in China and climate may be a potential risk factor for PDCoV infection. It is suggested that appropriate measures should be taken in different climatic areas to reduce local PDCoV infection.

The trogocytosis of neutrophils on initial transplanted tumor in mice.

The role of neutrophils in tumor initiation stage is rarely reported because of the lack of suitable models. We found that neutrophils recruited in early tumor nodules induced by subcutaneous inoculation of B16 melanoma cells were able to attack tumor cells by trogocytosis. The anti-tumor immunotherapy like peritoneal injection with TLR9 agonist CpG oligodeoxynucleotide combined with transforming growth factor ß2 inhibitor TIO3 could increase the trogocytic neutrophils in the nodules, as well as CD8+ T cells, natural killer (NK) cells, and their interferon-γ production. Local use of Cxcl2 small interfering RNA significantly reduced the number of neutrophils and trogocytic neutrophils in tumor nodules, as well as CD8+ T and NK cells, and also enlarged the nodules. These results suggest that neutrophils recruited early to the inoculation site of tumor cells are conducive to the establishment of anti-tumor immune microenvironment. Our findings provide a useful model system for studying the effect of neutrophils on tumors and anti-tumor immunotherapy.

Neutrophils recruited to immunization sites initiating vaccine-induced antibody responses by locally expressing BAFF.

Neutrophils played a key role in the innate immune responses. Less is known about whether and how the neutrophils recruited in the immunization sites affecting the vaccine-induced antibody responses. In the process of evaluating the efficacy of an oil-in-water emulsion-formulated vaccine in mice, we found that neutrophils were rapidly and massively recruited to immunization sites but were barely detected in the draining lymph nodes. Interestingly, B cell-activating factor (BAFF) was abundantly expressed in the recruiting neutrophils at a very early stage. The initial neutrophil-derived BAFF firstly brought about the B cell responses in the local part, then subsequently in lymphoid organs. Activated B cells produced more BAFF through TLR9-IRF5 signaling pathway, thereby amplifying the vaccine-induced antibody responses. Suppressing BAFF in the neutrophils could weaken the B cell activation and reduce the antibody production. The data indicate that vaccines endow neutrophils with the potential to orchestrate antibody responses at immunization sites.

The adjuvanticity of manganese for microbial vaccines via activating the IRF5 signaling pathway.

Manganese (Mn2+) has been reported to activate macrophages and NK cells, and to induce the production of type-I interferons (IFNs) by activating the cGAS-STING pathway. Few studies have been conducted on its adjuvanticity to microbial vaccines, and on the involvement of the interferon regulatory factor (IRF) 5 signaling pathway in the adjuvanticity. In this study, we demonstrated that Mn2+ could facilitate various microbial vaccines to induce enhanced antibody responses, and facilitate the influenza virus vaccine to induce protective immunity against the influenza virus challenge. When formulated in vaccines, Mn2+ could activate murine CD4+ T cells, CD8+ T cells, B cells and DCs, and induce the expression and phosphorylation of TANK-binding kinase 1 (TBK1) and IRF5 in the splenocytes of the immunized mice, resulting in the increased expression of type-I IFNs, TNF-α, B cell-activating factor of the TNF family (BAFF) and B lymphocyte-induced maturation protein-1 (Blimp-1). The induced TBK1 could recruit and bind the IRF5. Furthermore, the Mn2+ induced expression of IRF5 and Blimp-1 was prohibited by a IRF5 interfering oligonucleotide. The data suggest the Mn2+ could be used as a novel type of adjuvants for microbial vaccines, and the activation of IRF5 signaling pathway might involve in the adjuvanticity.