Search Results (239)

Glioblastoma (GBM) is a highly aggressive and heterogeneous brain tumor. Glioma stem-like cells (GSCs) play a central role in tumor progression, therapeutic resistance, and recurrence. Although immune cells are known to shape the GBM microenvironment, the impact of antigen-presenting-cell (APC) signature genes on tumor-intrinsic phenotypes remains underexplored. We analyzed both bulk- and single-cell RNA sequencing datasets of GBM to investigate the association between APC gene expression and tumor-cell states, including stemness and metabolic reprogramming. Signature scores were computed using curated gene sets related to APC activity, KEGG metabolic pathways, and cancer hallmark pathways. Protein–protein interaction (PPI) networks were constructed to examine the links between immune regulators and metabolic programs. The high expression of APC-related genes, such as HLA-DRA, CD74, CD80, CD86, and CIITA, was associated with lower stemness signatures and enhanced inflammatory signaling. These APC-high states (mean difference = –0.43, adjusted p < 0.001) also showed a shift in metabolic activity, with decreased oxidative phosphorylation and increased lipid and steroid metabolism. This pattern suggests coordinated changes in immune activity and metabolic status. Furthermore, TNF-α and other inflammatory markers were more highly expressed in the less stem-like tumor cells, indicating a possible role of inflammation in promoting differentiation. Our findings revealed that elevated APC gene signatures are associated with more differentiated and metabolically specialized GBM cell states. These transcriptional features may also reflect greater immunogenicity and inflammation sensitivity. The APC metabolic signature may serve as a useful biomarker to identify GBM subpopulations with reduced stemness and increased immune engagement, offering potential therapeutic implications. Full article

Background/Objectives: Anti-drug antibody (ADA) formation can impact the safety, pharmacokinetics, and/or efficacy of biotherapeutics, including monoclonal antibodies (mAbs). Current strategies for ADA/immunogenicity risk prediction of mAbs include in silico algorithms, T cell proliferation assays, MHC-associated peptide proteomics assays (MAPPs), and dendritic cell internalization assays. However, B cell-mediated responses are not assessed in these assays. B cells are professional antigen-presenting cells (APCs) and secrete antibodies toward immunogenic mAbs. Therefore, methods to determine B cell responses would be beneficial for immunogenicity risk prediction and may provide a more comprehensive assessment of risk. Methods: We used a PBMC culture method with the addition of IL-4, IL-21, B cell activating factor (BAFF), and an anti-CD40 agonist mAb to support B cell survival and activation. Results: B cells in this assay format become activated, proliferate, and secrete IgG. A panel of 51 antibodies with varying clinical immunogenicity rates were screened in this assay with IgG secretion used as a readout for immunogenicity risk. IgG secretion differed among test articles but did not correlate with the clinical immunogenicity rating. Conclusions: This dataset highlights the challenges of developing a B cell assay for immunogenicity risk prediction and provides a framework for further refinement of a B cell-based assay for immunogenicity risk prediction of mAbs. Full article

Developing an effective vaccine that is safer is the main focus in the field of cancer immunotherapy. Among other therapeutic approaches, cancer nanovaccination is formulated to deliver tumor adjuvant or antigen to the antigen-presenting cells (APCs) to prevent cancer relapse and metastasis. It has shown excellent efficacy in inhibiting cancer growth. Herein, we discussed various forms of nanovaccines, including lipid-based nanovaccines, metal-based nanovaccines, carbon nanotube-based nanovaccines, PLGA-based nanovaccines, exosome-based nanovaccines, dendritic cell-based nanovaccines, and self-adjuvant nanovaccines in cancer immunotherapy, including their therapeutic effect. We expect that the investigated content will provide a valuable reference for future research and the development of nanovaccines for cancer treatment. Full article

The activation of immunosuppressed antigen-presenting cells (APCs) in the tumor microenvironment is a key goal in modern cancer immunotherapy. Our laboratory utilizes a liposome-based immunotherapy platform that binds endogenous complement to deliver antigen, adjuvant, and therapeutic agents to APCs in vivo. The liposomes contain external linker groups, which readily bind complement protein C3, and mediate liposomal uptake via complement receptor 3 into APCs. To test the ability of a model antigen to bind to these external linker groups on C3-liposomes and elicit a robust adaptive immune response, we conjugated a modified ovalbumin peptide (OVA-C) to the liposomes and incorporated a toll-like receptor (TLR) 4 agonist, monophosphoryl lipid A (MPLA), in the liposomal membrane. Adaptive immune responses from C57BL/6 mice were analyzed by ELISA and ELISpot. Mice vaccinated with OVA-C liposomes elicited significantly greater humoral and cellular adaptive responses relative to controls. Furthermore, female mice vaccinated with MPLA + OVA-C liposomes produced significantly more IgG antibodies than males vaccinated with the same liposomes. In conclusion, antigen binding on the exterior of C3-liposomes markedly improves antigen loading efficiency and still allows for complement C3-targeted delivery to APCs. These data demonstrate the initiation of a robust cellular and humoral immune response using a new liposomal delivery platform. Full article

Background: In recent years, tumor vaccines have demonstrated unexpected success in cancer treatment. However, it still faces several challenges, including insufficient antigen and adjuvant delivery, unsuitable antigen delivery system, and inadequate antigen-presenting cell (APC) maturation. Antigenic adjuvant co-delivery tactics could be one way to enhance APC maturation. Methods: Membrane-fused nanovesicles were synthesized by separating melanoma cell membranes from BCG cytoplasmic membranes. Dynamic light scattering and transmission electron microscopy were used for measuring the vesicles’ size and shape. The uptake of vesicles by mouse bone marrow-derived dendritic cells and the activation of DC cells by vesicles were verified in vitro. In order to further confirm the material’s capacity to activate the immune system and its ability to inhibit tumor growth, the activation of DC and T cells in mouse draining lymph nodes and the concentration of anti-tumor cytokines were measured. Results: The hybrid vesicles were homogeneous in size and could facilitate phagocytosis by dendritic cells (DCs). They could also effectively activate DCs and T cells in vitro and in vivo, eliciting anti-tumor immunity. Moreover, the vesicles demonstrated satisfying biosafety with no major side effects. Conclusions: Motivated by the myth of the Trojan Horse, we created an antigen-adjuvant-integrated nanovesicle that merges the BCG cytomembrane with the tumor cell membrane, which can achieve immune cell stimulation and tumor antigen delivery simultaneously. In conclusion, these findings support the potential application of dual-membrane fusion nanovesicles as tumor vaccines. Full article

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors in the digestive tract, characterized by a high recurrence rate and inadequate immunotherapy options. We analyzed mutation data of ESCC from public databases and employed 10 machine learning algorithms to generate 101 algorithm combinations. Based on the optimal range determined by the concordance index, we randomly selected one combination from the best-performing algorithms to construct a prognostic model consisting of five genes (DLX5, MAGEA4, PMEPA1, RCN1, and TIMP1). By validating the correlation between the prognostic model and antigen-presenting cells (APCs), we revealed the antigen-presentation efficacy of the model. Through the analysis of immune infiltration in ESCC, we uncovered the mechanisms of immune evasion associated with the disease. In addition, we examined the potential impact of the five prognostic genes on ESCC progression. Based on these insights, we identified anti-tumor small-molecule compounds targeting these prognostic genes. This study primarily simulates the tumor microenvironment (TME) and antigen presentation processes in ESCC patients, predicting the role of the neoantigen-based prognostic model in ESCC patients and their potential responses to immunotherapy. These results suggest a potential approach for identifying therapeutic targets in ESCC, which may contribute to the development of more effective treatment strategies. Full article

Background: Mucin-1 (MUC1) is a glycoprotein that is hypoglycosylated and overexpressed in most adenocarcinomas, making it a promising target for cancer vaccines. Our group previously demonstrated that C3 (OPSS)-liposomes enhance antigen uptake by antigen-presenting cells (APCs) via the complement C3 pathway and, when combined with toll-like receptor (TLR) agonists, reduce tumor growth in murine cancer models. Methods: In the present study, we evaluate the immunogenicity of MUC1 peptide vaccines encapsulated in C3-liposomes, with and without TLR agonists, using MUC1-tolerant transgenic mice challenged with Lewis lung carcinoma (LLC.MUC1) cells. To assess vaccine effectiveness, tumor volumes were measured, and flow cytometry and ELISA and ELISPOT assays were used to assess the immune response. Results: Both male and female C57BL/6 transgenic mice vaccinated with MUC1 C3-liposomes developed significantly smaller tumors than those vaccinated with free MUC1 peptide or PBS. Notably, a sex-dependent response emerged in mice vaccinated with MUC1 C3-liposomes with TLR agonists (TLR4, TLR7/8, and TLR9); male mice exhibited greater tumor suppression than females. Flow cytometry analysis revealed that female mice had significantly higher levels of CD11b⁺, LY6C⁺, and LY6G⁺ MDSC cells, suggesting a potential mechanism for the sex difference. Additionally, MUC1 C3-liposome vaccination elicited robust adaptive immune responses, including significantly higher levels of IFN-γ-producing T cells and MUC1-specific IgG antibodies compared to non-encapsulated MUC1 or TLR adjuvant-only formulations. Conclusions: These findings underscore the potential of C3-liposome-based antigen vaccines to enhance anti-tumor immunity and highlight the impact of sex differences in vaccine efficacy. Full article

Belatacept is a chimeric protein that acts as a selective blocker of T-lymphocyte co-stimulation. It has been proposed for the prevention of kidney transplant rejection. This paper reports a literature review on pharmacological characteristics of belatacept and genetic factors influencing its efficacy and safety profile. A severe case of neurotoxoplasmosis observed in a kidney transplant recipient (KTR) treated with belatacept is also described. It appears that the interference of belatacept on guanylate binding proteins (GBPs) expression in antigen-presenting cells (APC) cytoplasm could be involved in Toxoplasma gondii (Toxo-g) reactivation in seropositive KTRs. Additionally, genetic variations in immune regulatory genes encoding CTLA-4 and Blimp-1 may influence individual susceptibility to infection and immune modulation under belatacept therapy. In conclusion, we highlight the importance of drug avoidance and/or increased surveillance in Toxo-g IgG-positive KTR. We also retain that further studies on the host defense pathways involved in the surveillance of opportunistic pathogens in KTR are strongly desirable. Full article

Background: Personalized cancer vaccines based on tumor neoantigens show great potential in cancer immunotherapy due to their high safety and specificity. However, it is inherently difficult to realize the efficiently targeted delivery of personalized cancer vaccines to antigen-presenting cells (APCs). Methods: This study aimed to address these challenges by developing and evaluating a personalized cancer vaccine based on antibody–antigen complexes, which was designed to enhance antitumor effects by increasing the utilization of tumor neoantigens by APCs. Mice were immunized with a carrier protein, keyhole limpet hemocyanin (KLH), to induce the production of antibodies against KLH. Subsequently, mice were immunized with KLH loaded with tumor neoantigens and the immunoadjuvant CpG ODN and underwent immunological analysis to evaluate the immune and antitumor effects. Results: The results showed that preimmunization with KLH could promote the uptake of the personalized KLH-based tumor vaccine, which was enhanced by dendritic cells (DCs) and macrophages (Mφs), by strengthening the T-cell immune responses to tumors. Conclusions: Collectively, this work provides a new idea for the targeted delivery of personalized cancer vaccines. Full article

Sepsis is a complex clinical syndrome closely associated with the occurrence of acute organ dysfunction and is often characterized by high mortality. Due to the rapid progression of sepsis, early diagnosis and intervention are crucial. Recent research has focused on exploring the pathological response involved in the process of sepsis. Liver sinusoidal endothelial cells (LSECs) are a special type of endothelial cell and an important component of liver non-parenchymal cells. Unlike general endothelial cells, which mainly provide a barrier function within the body, LSECs also have important functions in the clearance and regulation of the immune response. LSECs are not only vital antigen-presenting cells (APCs) in the immune system but also play a significant role in the development of infectious diseases and tumors through their specific immune regulatory pathways. However, in certain disease states, the functions of LSECs may be impaired, leading to immune imbalance and the development of organ failure. Investigating the immune pathways of LSECs in sepsis may provide new solutions for the prevention and treatment of sepsis and is crucial for maintaining microcirculation and improving patient outcomes. Full article

Background: Gold nanoparticles enhance immunity, promotes antigen uptake by antigen-presenting cells (APCs), and boost the response against tumor antigens; therefore, they are a promising delivery vehicle. Tumor lysates have shown favorable responses as inductors of anti-cancer immunity, but the effectiveness of these treatments could be improved. Hybrid nanosystems gold nanoparticles with biomolecules have been show promising alternative on uptake, activation and response on immune system. Objectives: This study’s objective was to develop a method of synthesizing gold nanoparticles employing a triple-negative breast cancer (4T1) cell lysate (AuLtNps) as a reducing agent to increase immunogenicity against breast cancer cells. Methods: Nanoparticle formation, size, and $\zeta$ potential were confirmed by surface plasmon resonance, dynamic light scattering, and transmission electron microscopy. Protein concentration was quantified using a Pierce BCA assay. The cytotoxic effects of treatments on murine macrophages were assessed, along with nanoparticle and tumor lysate uptake via epifluorescence microscopy. Using a murine model, cytokine secretion profiles were determined, and the efficacy in inhibiting the implantation of a 4T1 model was evaluated. Results/Conclusions: AuLtNps exhibited higher protein content than tumor lysate alone, leading to increased uptake and phagocytosis in murine macrophages, as confirmed by epifluorescence microscopy. Cytokine secretion analysis showed a proinflammatory response, with increased CD8+ and CD22+ lymphocytes and upregulation of APC markers (CD14, CD80, CD86, and MHC II+). Splenocytes demonstrated specific lysis of up to 40% against 4T1 tumor cells. In a murine model, AuLtNPs effectively inhibited tumor implantation, achieving an improved 90-days survival rate, highlighting their potential as an immunotherapy for triple-negative breast cancer. Full article

Retinal Müller glial cells (RMG) play a crucial role in retinal neuroinflammation, including autoimmune uveitis. Increasing evidence supports their function as active modulators of immune responses and potential atypical antigen-presenting cells (APCs). To further investigate this hypothesis, we conducted a differential proteome analysis of primary equine RMG from healthy controls and horses with equine recurrent uveitis (ERU), a spontaneous model of autoimmune uveitis. This analysis identified 310 proteins with differential abundance. Among these, the Major Histocompatibility Complex (MHC) class II and the enzyme Arginase 1 (ARG1) were significantly enriched in RMG from uveitis-affected horses, whereas Mannose Receptor C-type 2 (MRC2) and its interactor Thrombospondin 1 (THBS1) were more abundant in healthy RMG. The detection of MHC class II in equine RMG, consistent with previous studies, validates the robustness of our approach. Furthermore, the identification of ARG1 and MRC2, together with THBS1, provides new insights into the immunomodulatory and antigen-presenting properties of RMG. Immunohistochemical analyses confirmed the proteomic findings and revealed the spatial distribution of ARG1 and MRC2. ARG1 and MRC2 are thus markers for RMG in the neuroinflammatory or physiological milieu and highlight potential differences in the immune function of RMG, particularly in antigen presentation. Full article

Background/Objectives: Influenza vaccines require good thermal stability without the need for refrigerator storage. Although the fatty acid-conjugated hemagglutinin (Heg) vaccine antigen provides good stability in both solid and liquid states, its therapeutic effectiveness must be validated in vivo. This study aimed to investigate the immunogenicity of the thermally stabilized Heg-oleic acid conjugate (HOC) and compare it with native Heg as a reference. Method: To evaluate HOC immunogenicity, an enzyme-linked immunosorbent assay was used to measure hemagglutinin inhibition (HI) titers, serum IgG antibody titers (IgG1, IgG2a), and cytokine secretion levels (IFN-γ, IL-4) in BALB/c mice after intramuscular (IM) injection. Results: Thermally stabilized HOC induced higher and more sustained serum IgG1 and IgG2a responses than the native Heg vaccine antigen. IgG1 is typically associated with a Th2 response, whereas IgG2a is associated with a Th1 response. HOC appeared to enhance both responses, inducing a more balanced immune response. Moreover, HOC antigens stimulate broader immune responses, suggesting stronger and longer-lasting immune memory. The cytokine levels of IFN-γ (2.8-fold) and IL-4 (6-fold) were significantly increased in the HOC-immunized group compared to the Heg group. IFN-γ, a cytokine that activates the Th1 immune response, demonstrated the enhanced ability of HOC to induce a Th1 response. IL-4, a cytokine that promotes the Th2 response, indicated that HOC also strongly induced a Th2 response. The thermal stability of HOC antigens was crucial for maintaining their structural integrity, enabling the continuous exposure to the stable antigen without denaturation. This allows immune cells to recognize stable antigens efficiently and form long-term immune memory. Conclusions: The stability of HOC antigens enhanced the antigen processing efficiency of antigen-presenting cells (APCs) and stimulated immune responses. The fatty acid-conjugated vaccine antigen could provide improved storage stability but also enhance immunogenic efficacy compared to the native antigen, supporting its potential for further applications. Full article

The occurrence and severity of periodontitis (PD) tend to increase with age, and yet the underlying mechanisms remain unclear. Immune senescence is known to be triggered in mice and humans as they age. Experimental PD in mice has been shown to induce senescence biomarkers p16 ^INK4a and p21, dysfunction of antigen-presenting cells (APCs), and activation of the senescence-associated secretory phenotype (SASP). However, the causal links of senescence to experimental PD are not yet established. This study aims to elucidate the role of senescence in experimental PD at a causal level. The P16-3MR mouse model harbors the p16^INK4a (Cdkn2a) promoter, driving in vivo expression of synthetic Renilla luciferase, monomeric red fluorescent protein (mRFP), and herpes simplex virus-1 thymidine kinase (HSV-TK). This facilitates in vivo identification of p16 ^INK4a activation at the cellular level and the consequences of selective elimination of p16^INK4a-positive cells by ganciclovir (GCV) treatment. Mice were treated with/without GCV for two weeks during ligature-induced PD. In vivo bioluminescence imaging quantified p16^INK4a activation, while Western blot and immunofluorescence analyses assessed key senescence and inflammatory markers (p16, p21, p53, Cyclin D1, p-H2A.X, IL17, and IL1β). Alveolar bone volume was analyzed by micro-CT and histomorphometry. Our findings demonstrate that clearance of senescent cells in mice subjected to experimental PD alleviates inflammation and mitigates bone loss. These results suggest a causal role for senescence in PD pathology, raising the future prospect of senolytic agents for therapeutic intervention in PD. Full article

For a better understanding of classical swine fever (CSF) pathogenesis, a transcriptomic analysis was performed using porcine bone marrow (BM)-derived antigen-presenting cells (APCs) infected ex vivo with two different cDNA-derived classical swine fever virus (CSFV) strains, the low-virulence Pinar de Rio (vPdR-36U) or the lethal vPdR-H₃₀K-5U. The transcriptomic profile of vPdR-36U- or vPdR-H₃₀K-5U-infected versus noninfected cells revealed 946 and 2643 differentially expressed genes (DEGs), respectively. The upregulation of ISG15, CXCL-10, ADAM8, and CSF1 was found after infection with vPdR-36U, which could contribute to the generation of mild CSF forms. In contrast, cells infected with the lethal vPdR-H₃₀K-5U overexpressed the immune checkpoint molecules PD-L1, CD276, and LAG3, which are involved in T-cell exhaustion and could be associated with adaptive immunity impairment. vPdR-H₃₀K-5U also induced increased expression of PPBP, IL-8, IL-6, ECE1, and Rab27b, which are mediators of inflammatory responses that can be involved in cytokine storms. The TNF signaling pathway, which is related to the activation and proliferation of different subsets of immune cells, including CD4+ T cells, was notably upregulated in response to the low-pathogenicity virus. The Th17, Th1, and Th2 differentiation pathways were downregulated by the highly pathogenic virus only, supporting the role of T-cell-mediated immunity in protecting against CSFV. Full article