Search Results (318)

Myxoma virus (MYXV), a rabbit-specific poxvirus and non-pathogenic in humans and mice, is an excellent candidate oncolytic virus for cancer therapy. MYXV also has immunotherapeutic benefits. In ovarian cancer (OC), immunosuppressive tumor-associated macrophages (TAMs) are key to inhibiting antitumor immunity while hindering therapeutic benefit by chemotherapy and dendritic cell (DC) vaccine. Because MYXV favors binding/entry of macrophages/monocytes, we examined the therapeutic potential of MYXV against TAMs. We found previously that a replication-defective MYXV with targeted deletion of an essential gene, M062R, designated ΔM062R MYXV, activated both the host DNA sensing pathway and the SAMD9 pathway. Treatment with ΔM062R confers therapeutic benefit comparable to that of wild-type replicating MYXV in preclinical models. Here we found that ΔM062R MYXV, when integrated with cisplatin and DC immunotherapy, further improved treatment benefit, likely through promoting tumor antigen-specific T cell function. Moreover, we also tested ΔM062R MYXV in targeting human immunosuppressive TAMs from OC patient ascites in a co-culture system. We found that ΔM062R treatment subverted the immunosuppressive properties of TAMs and elevated the avidity of cytokine production in tumor antigen-specific CD4⁺ T cells. Overall, ΔM062R presents a promising immunotherapeutic platform as a beneficial adjuvant to chemotherapy and DC vaccine. Full article

Viral infections persistently challenge global health through immune evasion and zoonotic transmission. Dendritic cells (DCs) play a central role in antiviral immunity by detecting viral nucleic acids via conserved pattern recognition receptors, triggering interferon-driven innate responses and cross-presentation-mediated activation of cytotoxic CD8⁺ T cells. This study synthesizes DC-centric defense mechanisms against viral subversion, encompassing divergent nucleic acid sensing pathways for zoonotic DNA and RNA viruses, viral counterstrategies targeting DC maturation and interferon signaling, and functional specialization of DC subsets in immune coordination. Despite advances in DC-based vaccine platforms, clinical translation is hindered by cellular heterogeneity, immunosuppressive microenvironments, and limitations in antigen delivery. Future research should aim to enhance the efficiency of DC-mediated immunity, thereby establishing a robust scientific foundation for the development of next-generation vaccines and antiviral therapies. A more in-depth exploration of DC functions and regulatory mechanisms may unlock novel strategies for antiviral intervention, ultimately paving the way for improved prevention and treatment of viral infections. Full article

Cutaneous melanoma is an aggressive cancer with an increasing incidence worldwide, highlighting the need for research into its pathogenesis. The tumor microenvironment (TME) plays a critical role in melanoma progression and consists of cellular components and an extracellular matrix (ECM) rich in cytokines and signaling molecules. The most abundant stromal cells within the TME are cancer-associated fibroblasts (CAFs), which remodel the ECM and modulate immune responses. Among immune cells, tumor-associated macrophages (TAMs) predominate, and their polarization toward the M2 phenotype supports tumor progression. Tumor-infiltrating lymphocytes (TILs) have diverse functions, including cytotoxic T-cells, helper T-cells that modulate immune response, B-cells forming tertiary lymphoid structures (TLS), and regulatory T-cells with immunosuppressive properties. Dendritic cells (DCs) also play a complex role in the TME. A notable subpopulation are mature regulatory dendritic cells (mregDCs), which contribute to immune evasion. All of these TME components may drive tumorigenesis. Advancements in melanoma treatment—including immunotherapy and targeted therapies—have significantly improved outcomes in advanced-stage disease. In parallel, emerging approaches targeting the tumor microenvironment and gut microbiome, as well as personalized strategies such as neoantigen vaccines and cell-based therapies, are under active investigation and may further enhance therapeutic efficacy in the near future. Full article

Background/Objectives: Pancreatic cancer remains the fourth leading cause of cancer-related deaths. While peripheral blood-derived mature dendritic cell (mDC) vaccines have shown potential in eliciting anti-tumor immune responses, clinical efficacy has been limited. This study aimed to enhance the potency and scalability of DC-based immunotherapy by developing an allogeneic DC platform derived from CD34⁺ hematopoietic stem cells (HSCs), genetically engineered to overexpress CD93, CD40L, and CXCL13, followed by maturation and tumor antigen pulsing. Methods: Engineered DCs were generated from CD34⁺ HSCs and matured in vitro after lentiviral transduction of CD93, CD40L, and CXCL13. Tumor lysates were used for antigen pulsing. A scrambled-sequence control DC was used for comparison. In vitro assays were performed to assess T cell activation and tumor cell killing. In vivo efficacy was evaluated using orthotopic pancreatic tumors in BLT and PBMC-humanized NSG mice established with the MiaPaca-2 (MP2) cell line. Results: Engineered DCs significantly enhanced T cell activation and tumor-specific cytotoxicity in vitro compared to control DCs. Antigen pulsing further amplified immune activation. In vivo, treated humanized mice showed increased CD4⁺, CD8⁺, and NK cell frequencies in peripheral blood and within tumors, correlating with reduced tumor burden. Conclusions: Our data shows that the antigen-pulsed, engineered DCs have the potency to activate immune cells, which leads to a significant reduction in pancreatic tumors and therefore could potentially provide an effective therapeutic opportunity for the treatment of pancreatic cancer and other solid tumors. Full article

Introduction: Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Even though surgery and chemotherapy are the mainstay of treatment, immunotherapy, and more specifically anti-tumor vaccination, has gained popularity over the past years due to the lower related toxicity and fewer long-term side effects. Dendritic cell (DC) vaccines have been shown to induce tumor specific cytotoxic T-cell (CTL) responses both in vitro and in vivo; however, due to the nature of the disease, resistance to immunotherapy is often developed. Various modifications, such as the implementation of viral vectors, tumor RNA, or even tumor-specific peptides (neoantigens), have been studied as a means to avoid resistance and enhance the effectiveness of the vaccines. In this review, we aim to assess the effects of neoantigen-loaded DC vaccines (naDCVs) on the immune response against gastric cancer cells. Materials and methods: A thorough literature search was conducted on PubMed and clinicaltrials.gov for studies assessing the efficacy of naDCVs against gastric cancer both in vivo and in vitro. The studies were assessed for eligibility by two independent reviewers based on predetermined inclusion and exclusion criteria. The search was completed following the PRISMA guidelines. Results: Eleven studies were included in our systematic review. In five of the studies, the effects of the naDCVs were tested in vitro; in two and in four they were examined both in vitro and in vivo. The in vitro studies showed that the naDCVs resulted in a more robust immune response against the cancer cells in the study groups compared to the control groups. The in vivo studies conducted on mice showed that tumor volume was reduced in the groups treated with the naDCV compared to the untreated groups. What is more, the cytotoxic effect of CTLs against tumor cells was also increased in the vaccine groups. One of the studies was conducted on humans as a phase I study. The results show increased CTL proliferation and cytokine production in the vaccinated group compared to the control, but no difference regarding the tumor size was observed. Conclusions: Neoantigen-loaded DC vaccines can stimulate a strong immune response against specific gastric cancer cell peptides and enhance tumor cell lysis, therefore hindering or even reversing disease progression, offering great potential for the treatment of patients with gastric cancer. Full article

Although vaccine development has primarily focused on inducing neutralizing antibodies, increasing evidence supports an important role of CD8⁺ T cell responses in vaccine effectiveness. Routine assays, which are mainly based on antibody titers, may therefore not accurately reflect the full immune response elicited by vaccination. Assessing antigen-specific T cell responses upon vaccination poses several challenges. A common issue in studying T cells specific to a vaccine antigen is their low frequency in circulation, which can limit their ex vivo analysis. Moreover, the use of human cell-based models is crucial for studying and optimizing the induction of T cell responses to design effective vaccines. We developed an innovative in vitro approach of human CD8⁺ T cell priming, based on the rapid mobilization of dendritic cells (DCs) directly from unfractionated peripheral blood mononuclear cells (PBMCs). This simple and original method allows for side-by-side comparisons of multiple test parameters in a standardized system, providing both quantitative and qualitative readouts of primed antigen-specific CD8⁺ T cells. Here, we discuss the genesis of this approach and its versatile applications, including monitoring antigen-specific T cell responses, evaluating an individual’s T cell priming capacity, and conducting preclinical studies on potential adjuvants and vaccine candidates. Full article

Background: While mRNA vaccines effectively limit hospitalization and severe COVID-19 disease, the precise early innate immune mechanisms associated with their efficacy and reactogenicity remain underexplored. The identification of innate immune correlates prior to vaccination could provide mechanistic insights and potentially predict responses. Methods: We developed an in vitro model to study the innate immune activation of pre-vaccination peripheral blood mononuclear cells (PBMCs) collected from participants enrolled in a well-characterized COVID-19 BioNTech/Pfizer BNT162b2 vaccine (BNT162b2 vaccine) cohort. Pre-vaccination PBMCs were stimulated with empty lipid nanoparticle (LNP), mRNA-LNP, or Toll-like receptor (TLR) agonists. Using multiparameter spectral flow cytometry, we analyzed the baseline immune state, innate responsiveness to stimuli, and cytokine profiles of study participants. These pre-vaccination in vitro results were analyzed for correlations with post-vaccination symptoms and spike-specific IgG responses. Results: Baseline dendritic cell (DC) states inversely correlated with the magnitude of symptoms following BNT162b2 vaccination. Heightened conventional (cDC) and weaker plasmacytoid DC (pDC) responses to RNA stimuli correlated with the magnitude of an acute IgG response. IgG durability modestly correlated with a lower pDC state but higher cDC2 and monocyte baseline states and inversely correlated with TLR3 agonist responsiveness. Conclusions: The pre-vaccination assessment of innate immune function and resting states can be used to fit models potentially predictive of immunogenicity and reactogenicity to BNT162b2 vaccination. Pre-vaccination DC states may influence reactogenicity, while the response to RNA may impact antibody responses. Our data suggest that pre-vaccination assessment offers insights into the innate mechanisms driving mRNA vaccine responses and has predictive potential. Full article

Glycogen synthase kinase-3 (GSK-3)—particularly the GSK-3β isoform—plays a pivotal role in regulating dendritic cell (DC) functions, including maturation, cytokine production, and antigen presentation. In immature DCs, GSK-3β is continuously active, and its inhibition has been shown to enhance DC maturation and function. As a key upstream kinase of β-catenin, GSK-3 inhibition activates β-catenin in both human and murine DCs—a pathway traditionally linked to its immunomodulatory effects. However, our recent findings challenge this paradigm by uncovering β-catenin-independent, dual roles of GSK-3β in DCs. Our study reveals that while GSK-3β enhances DC-mediated cross-priming of CD8 T cells, it concurrently impairs the generation of memory CD8 T cells. These findings have significant implications for vaccine development and cancer immunotherapy, where both effective T-cell priming and durable memory responses are critical. This mini-review provides an in-depth analysis of mechanistic insights into GSK-3β’s paradoxical functions and discusses potential strategies to fine-tune GSK-3 activity for optimized immunotherapeutic outcomes. Full article

Cancer continues to pose a significant challenge to global health, resulting in millions of deaths annually despite advancements in treatments like surgery, chemotherapy, and radiotherapy. A key factor complicating successful outcomes is the presence of cancer stem cells (CSCs), which possess distinctive features that facilitate tumor initiation and progression as well as resistance to therapies. These cells are adept at evading conventional treatments and can hinder the effectiveness of immunotherapy, often manipulating the tumor microenvironment to suppress immune responses. This review delves into the complex interplay between CSCs and immune cells, emphasizing their contributions to tumor heterogeneity and therapeutic resistance. By investigating the CSC niche in which these cells thrive and their complex interactions with the immune system, we aim to reveal new therapeutic avenues that could enhance patient outcomes and minimize the risk of recurrence. CSCs are characterized by remarkable self-renewal and plasticity, allowing them to transition between stem-like and differentiated states in response to various stimuli. Their existence within the CSC niche confers immune protection and maintains stem-like properties while promoting immune evasion. Activating key signaling pathways and specific surface markers is crucial in developing CSC traits, pointing to potential strategies for effective tumor eradication. Conventional therapies often fail to eliminate CSCs, which can lead to tumor recurrence. Therefore, innovative immunotherapeutic strategies such as dendritic cell vaccines (DC vaccines), chimeric antigen receptor (CAR) engineered T cells, and immune checkpoint inhibitors (ICIs) are under examination. This review sheds light on CSC’s roles across different malignancies, highlighting the necessity for innovative targeted approaches in cancer treatment. Full article

Dendritic cell (DC) vaccines stimulate the immune system to target cancer antigens, representing a promising option for immunotherapy. However, clinical trials have demonstrated limited effectiveness, emphasizing the need for enhanced immune responses. Improving the production of DC vaccines, assessing their impact on immune components, and observing responses could improve the results of DC-based therapies. Innate lymphoid cells (ILCs) represent a heterogeneous population of innate immune components that generate cytokines and modulate the immune system, potentially enhancing immunotherapies. Recent research highlights the different functions of ILCs in cancer, demonstrating their dual capabilities to promote tumors and exhibit anti-tumor actions. DCs and ILCs actively communicate under physiological and pathological conditions, and the activation of ILCs by DCs or DC vaccines has been shown to influence ILC cytokine production and function. Gaining insights into the interaction between DC-activated ILCs and tumors is essential for creating exciting new therapeutic strategies. These strategies aim to boost anti-tumor immunity while reducing the support that tumors receive. This review examines the effect of DC vaccination on host ILCs, illustrating the complex relationship between DC-based vaccines and ILCs. Furthermore, it explores some exciting strategies to enhance DC vaccines, aiming to boost anti-tumor immune responses by fostering better engagement with ILCs. Full article

Background/Objectives: Breast cancer remains a leading cause of cancer-related mortality among women worldwide, necessitating novel therapeutic strategies. This study aimed to investigate the synergistic antitumor effects of caerin peptides (F1/F3) combined with dendritic cell (DC) vaccines in a 4T-1 murine breast cancer model, providing new insights for breast cancer immunotherapy. Methods: In vitro experiments evaluated the effects of F1/F3 on 4T-1 cell proliferation and apoptosis. A 4T-1 breast cancer mouse model was established, and treatments included F1/F3 alone, DC vaccines (DCV₁: loaded with whole tumor antigens; DCV₂: loaded with F1/F3-induced apoptotic antigens), or combination therapy. Flow cytometry analyzed immune cell subsets in the tumor microenvironment and lymph nodes, while ELISA measured cytokine levels. Results: F1/F3 significantly inhibited 4T-1 cell proliferation and induced apoptosis while suppressing tumor growth and lung metastasis in vivo. Flow cytometry revealed increased infiltration of CD4⁺ T cells and cDC₁ in tumors, along with reduced PD-L1 expression. DCV₂ exhibited stronger T-cell proliferation induction and lower IL-10 secretion in vitro. Combination therapy with DCV₂ and F1/F3 demonstrated superior tumor suppression compared to monotherapy. Conclusions: F1/F3 enhances antitumor immunity by modulating the tumor microenvironment, and its combination with DCV₂ yields synergistic effects. This study provides experimental evidence for combination immunotherapy in breast cancer, with potential for further optimization of DC vaccine design to improve efficacy. Full article

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines the biological functions of DC subsets (cDC1, cDC2, pDC, and moDC) and their roles in initiating and modulating immune responses against HCC. We detail the mechanisms underlying DC impairment within the TME, including suppression by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). Additionally, we discuss novel DC-based therapeutic strategies, such as DC-based vaccines designed to enhance antigen presentation and T cell activation. Combining DC vaccines with immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 blockers, demonstrates synergistic effects that can overcome immune evasion and improve clinical outcomes. Despite progress, challenges related to DC subset heterogeneity, TME complexity, and patient variability require the further optimization and personalization of DC-based therapies. Future research should focus on refining these strategies, leveraging advanced technologies like genomic profiling and artificial intelligence, to maximize therapeutic efficacy and revolutionize HCC treatment. By restoring DC function and reprogramming the TME, DC-based immunotherapy holds immense potential to transform the management of HCC and improve patient survival. Full article

Dendritic cells (DCs) are major contributors to generating an effective immune response due to their ability to present antigens to T cells. Recently, nanoparticles have been widely used in different medical applications, such as drug-delivery systems, to enhance the function of impaired immune cells. Objectives: This research aims to develop an effective antitumor DC-based vaccine by adsorption of chitosan-nanoparticles (CH-NPs) onto DCs. Methods: Undifferentiated mouse bone marrow progenitor cells were differentiated into mature DCs using cytokines and lipopolysaccharides. CH-NPs were prepared using the ionic gelation method and subsequently used to coat the stimulated DCs. The MTT assay was employed to assess the cytotoxicity of all formulations. To compare the antitumor effect of CH-NPs, DCs, and DCs-CH-NPs, mice were divided into five groups and injected with the respective vaccine formulations. Following immunization, flow cytometry was used to analyze DC and CD4⁺ T cell activation in blood and spleen tissues. Histological samples from the spleen and lymph nodes were also collected. Results: Our findings show that co-stimulatory molecules CD80/CD86 and the DC maturation marker CD83 were upregulated in the vaccinated DCs, indicating their maturation. Moreover, CD83, CD11c, and MHC-II were upregulated in blood and spleen samples in vivo. The DC-CH-NPs vaccinated group had a higher mean percentage of CD83 expression in blood samples (76.7 ± 17.1) compared to the DCs group (47.7 ± 11.0) and the CH-NPs group (37.7 ± 8.6). DC markers, particularly CD83, were highly expressed in spleen samples. Additionally, the DC-CH-NPs vaccinated group had a significantly higher number of CD4⁺ T cells (MFI = 26.1 ± 2.3) compared to the DCs (18.6 ± 1.6) and CH-NPs (13.3 ± 1.4) groups. Conclusions: The present study concludes that the DC-CH-NPs vaccine formulation can induce a potent in vivo immune response. These data may provide valuable insights for developing effective delivery systems for antitumor vaccines. Full article

Background: Influenza virus is one of the major respiratory virus infections that is a global health concern. Although there are already approved vaccines, most are administered via the intramuscular route, which is usually painful, leading to vaccine hesitancy. To this end, exploring the non-invasive, transdermal vaccination route using dissolving microneedles would significantly improve vaccine compliance. Research on innovative vaccine delivery systems, such as antigen-loaded PLGA microparticles, has the potential to pave the way for a broader range of vaccine candidates. Methods: In this proof-of-concept study, a combination of the inactivated influenza A H1N1 virus and inactivated influenza A H3N2 virus were encapsulated in a biodegradable poly (lactic-co-glycolic acid) (PLGA) polymeric matrix within microparticles, which enhanced antigen presentation. The antigen PLGA microparticles were prepared separately using a double emulsion (w/o/w), lyophilized, and characterized. Next, the vaccine microparticles were assessed in vitro in dendritic cells (DC 2.4) for immunogenicity. To explore pain-free transdermal vaccination, the vaccine microparticles were loaded into dissolving microneedles and administered in mice (n = 5). Results: Our vaccination study demonstrated that the microneedle-based vaccine elicited strong humoral responses as demonstrated by high antigen-specific IgA, IgG, IgG1, and IgG2a antibodies in serum samples and IgA in lung supernatant. Further, the vaccine also elicited a strong cellular response as evidenced by high levels of CD4+ and CD8a+ T cells in lymphoid organs such as the lymph nodes and spleen. Conclusion: The delivery of influenza vaccine-loaded PLGA microparticles using microneedles would be beneficial to individuals experiencing needle-phobia, as well as the geriatric and pediatric population. 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