Activation Of Antigen-presenting Cells Research Articles

Mn and Zn-Doped Multivariate Metal-Organic Framework as a Metalloimmunological Adjuvant to Promote Protection Against Tuberculosis Infection.

A first-in-class vaccine adjuvant delivery system, Mn-ZIF, is developed by incorporating manganese (Mn) into the zinc-containing zeolitic-imidazolate framework-8 (ZIF-8). The mixed metal approach, which allowed for tunable Mn doping, is made possible by including a mild reducing agent in the reaction mixture. This approach allows up to 50% Mn, with the remaining 50% Zn within the ZIF. This multivariate approach exhibits significantly decreased cytotoxicity compared to ZIF-8. The porous structure of Mn-ZIF enables the co-delivery of the STING agonist cyclic di-adenosine monophosphate (CDA) through post-synthetic loading, forming CDA@Mn-ZIF. The composite demonstrated enhanced cellular uptake and synergistic activation of the cGAS-STING pathway, producing proinflammatory cytokines and activating antigen-presenting cells (APCs). In a preclinical Mycobacterium tuberculosis (Mtb) model, CDA@Mn-ZIF formulates with the CysVac2 fusion protein elicited a potent antigen-specific T-cell response and significantly reduced the mycobacterial burden in the lungs of infected mice. These findings highlight the potential of CDA@Mn-ZIF as a promising adjuvant for subunit vaccines, offering a novel approach to enhancing vaccine efficacy and protection against infectious diseases such as tuberculosis.

Poria cocos polysaccharide-honeycomb manganese oxide nanoparticles as a vaccine adjuvant to induce potent immune responses

As indispensable components of vaccines, adjuvants play a critical role in inducing potent immune responses. In our previous study, we isolated and purified a water-soluble polysaccharide from Poria cocos (PCP), and found that the PCP had the potential to act as an immunostimulant to induce a balanced Th1/Th2 immune response. However, the PCP showed effective immunomodulatory activity only at high concentrations. Herein, we prepared a novel and biodegradable adjuvant system (PCP-hMnOx), in which the PCP was loaded onto the honeycomb manganese oxide nanoparticles (hMnOx). The developed PCP-hMnOx adjuvant system not only acted as an immunostimulant, but also as a delivery system to enhance antigen uptake by antigen-presenting cells (APCs), stimulate the activation of APCs and facilitate the formation of germinal center in draining lymph nodes. Furthermore, the PCP-hMnOx adjuvant system facilitated the antibody production, the activation of CD4+ and CD8+ T cells, and the generation of IFN-γ, thus inducing a robust and durable immune response with a balanced Th1/Th2 response in comparison to commercial alum adjuvant. Our results demonstrated that the PCP-hMnOx adjuvant system improved the immunomodulatory activity of the PCP, and had the potential to provide a simple, safe, and efficient nanoparticles-based strategy to induce potent immune responses.

TGF-β Score based on Silico Analysis can Robustly Predict Prognosis and Immunological Characteristics in Lower-grade Glioma: The Evidence from Multicenter Studies.

Nowadays, mounting evidence shows that variations in TGF-β signaling pathway-related components influence tumor development. Current research has patents describing the use of anti-TGF-β antibodies and checkpoint inhibitors for the treatment of proliferative diseases. Importantly, TGF-β signaling pathway is significant for lower-grade glioma (LGG) to evade host immunity. Loss of particular tumor antigens and shutdown of professional antigenpresenting cell activity may render the anti-tumor response ineffective in LGG patients. However, the prognostic significance of TGF-β related genes in LGG is still unknown. We collected RNA-seq data from the GTEx database (normal cortical tissues), the Cancer Genome Atlas database (TCGA-LGG), and the Chinese Glioma Genome Atlas database (CGGA-693 and CGGA-325) for conducting our investigation. In addition, previous publications were explored for the 223 regulators of the TGF-β signaling pathway, and 30 regulators with abnormal expression in TCGA and GTEx database were identified. In order to identify hub prognostic regulators, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis were used to screen from differentially expressed genes (DEGs). On the basis of 11 genes from LASSO-Cox regression analysis (NEDD8, CHRD, TGFBR1, TP53, BMP2, LRRC32, THBS2, ID1, NOG, TNF, and SERPINE1), TGF-β score was calculated. Multiple statistical approaches verified the predictive value of the TGF-β score for the training cohort and two external validation cohorts. Considering the importance of the TGF-β signaling pathway in immune regulation, we evaluated the prediction of the TGF-β score for immunological characteristics and the possible application of the immunotherapeutic response using six algorithms (TIMER, CIBERSORT, QUANTISEQ, MCP-counter, XCELL and EPIC) and three immunotherapy cohorts (GSE78820, Imvigor-210 and PRJEB23709). Notably, we compared our risk signature with the signature in ten publications in the meta-cohort (TCGA-LGG, CGGA-693 and CGGA-325), and the TGF-β score had the best predictive efficiency (C-index =0.812). In conclusion, our findings suggest that TGF-β signaling pathway-related signatures are prognostic biomarkers in LGG and provide a novel tool for tumor microenvironment (TME) assessment.

Modulation of antigen delivery and lymph node activation in nonhuman primates by saponin adjuvant saponin/monophosphoryl lipid A nanoparticle.

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in nonhuman primates (NHPs) comparing the most common clinical adjuvant aluminum hydroxide (alum) with saponin/monophosphoryl lipid A nanoparticles (SMNP), an immune-stimulating complex-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B-cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells. Positron emission tomography and computed tomography imaging in live NHPs showed that, unlike alum, SMNP promoted rapid antigen accumulation in both proximal and distal lymph nodes (LNs). SMNP also induced strong type I interferon transcriptional signatures, expansion of innate immune cells, and increased antigen-presenting cell activation in LNs. These findings indicate that SMNP promotes multiple facets of the early immune response relevant for enhanced immunity to vaccination.

Biomimetic Nanovaccines Restore Immunosuppressive Tumor Antigen-Presenting Cells via the Saposin-Feeding Strategy.

Cancer cell membrane-derived biomimetic nanovaccines have shown tremendous potential in cancer immunotherapy. However, their efficacy is restricted by the insufficient cross-presentation of cell membrane-associated antigens. Saposins (SAs), which are vital for membrane vesicle disintegration and cell membrane-associated antigen presentation, are severely deficient in the antigen-presenting cells (APCs) within tumors. Herein, we propose a complementary strategy for increasing the efficacy of biomimetic nanovaccines via the use of SAs. Biomimetic nanovaccines were designed using cancer cell membrane shells to provide a comprehensive array of tumor-associated antigens and reactive oxygen species (ROS)-responsive nanoparticle cores that allowed the codelivery of cytosine-guanine dinucleotides (CpGs) and SAs. The biomimetic nanovaccines were ROS-responsive and highly internalized by APCs, which enabled the release of CpGs and SAs in the endo/lysosomes of APCs. Furthermore, biomimetic nanovaccines increased the activation of immunosuppressive APCs and enhanced T-cell priming by delivering SAs to the APCs. Consequently, biomimetic nanovaccines loaded with SAs not only suppressed tumor growth but also exhibited excellent therapeutic effects in combination with immune checkpoint blockade strategies. Overall, our study provides insights into the development of enhanced biomimetic nanovaccines via integrating SAs and offers a promising strategy for highly effective cancer immunotherapy.

Reprogramming cellular senescence in the tumor microenvironment augments cancer immunotherapy through multifunctional nanocrystals.

Harnessing the immunogenic potential of senescent tumor cells provides an opportunity to remodel tumor microenvironment (TME) and boost antitumor immunity. However, this potential needs to be sophisticatedly wielded to avoid additional immunosuppressive capacity of senescent cells. Our study shows that blocking the JAK2/STAT3 pathway enhances immunogenic efficacy of Aurora kinase inhibitor alisertib (Ali)-induced senescence by reducing immunosuppressive senescence-associated secretory phenotype (SASP) while preserving immunogenic SASP. Hypothesizing that SASP reprogramming with Ali and JAK2 inhibitor ruxolitinib (Rux) will benefit cancer immunotherapy, we create nanoparticulate crystals (Ali-Rux) composed of Ali and Rux with a fully active pharmaceutical ingredient. Immunization with Ali-Rux-orchestrated senescent cells promotes stronger activation of antigen-presenting cells, enhancing antitumor immune surveillance. This approach remodels the TME by increasing CD8+ T cell and NK recruitment and activation while decreasing MDSCs. Combined with PD-L1 blockade, Ali-Rux elicits a durable antitumor immune response, suggesting the TME reshaping approach as a potential cancer immunotherapy.

Myeloid-Specific JAK2 Contributes to Inflammation and Salt Sensitivity of Blood Pressure.

Salt sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific JAK2 (Janus kinase 2) through STAT3 (signal transducer and activator of transcription 3) and SMAD3 (small mothers against decapentaplegic homolog 3) contributes to SSBP. We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP. We also used a myeloid cell-specific CD11c+ JAK2 knockout mouse model and measured blood pressure with radiotelemetry after N-omega-nitro-L-arginine-methyl ester and a high salt diet treatment. We used flow cytometry for immunophenotyping and measuring cytokine levels. Fluorescence in situ hybridization and immunohistochemistry were performed to spatially visualize the kidney's immune cells and cytokine levels. Echocardiography was performed to assess cardiac function. We found that high salt treatment upregulates gene expression of the JAK/STAT/SMAD pathway while downregulating inhibitors of this pathway, such as suppression of cytokine signaling and cytokine-inducible SH2, in human monocytes. Expression of the JAK2 pathway genes mirrored changes in blood pressure after salt loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11c+ APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acted downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and proinflammatory cytokine IL (interleukin)-6 in renal APCs, which activate T cells and increase production of IL-17A, IL-6, and TNF-α (tumor necrosis factor-alpha). Our findings reveal the APC JAK2 signaling pathway as a potential target for the diagnosis and treatment of SSBP in humans.

Hemophagocytic Lymphohistiocytosis (HLH)

HLH is a reactive process resulting from prolonged and excessive antigen-presenting cell activation [1]. Hemophagocytosis is a hallmark of activated macrophages/histiocytes. The predominant clinical findings of HLH are fever (often hectic and persistent), cytopenia, hepatitis, and splenomegaly. A case of HLH in a 32-year-old female with no past medical history was presented in the current paper. She was admitted to the medical department with a fever and thrombocytopenia for evaluation. After failure to respond to a brief course of empiric antibiotics, the patient was extensively investigated and finally diagnosed with HLH (bone marrow aspiration showed occasional hemophagocytes). She was started on steroids but, failed to respond and so immunosuppressant drugs were added to the therapy.

Bacterial ghosts engineered with lipidated antigens as an adjuvant-free vaccine for Chlamydia abortus

Bacterial ghosts (BGs) provide novel vaccine delivery platforms because of their inherent adjuvant properties and efficient antigen delivery capabilities. However, effective engineering strategies are required to modify them for different antigens. In this study, the Escherichia coli (E. coli) ghost was modified by using a lpp’-ompA chimera, a widely used bacterial surface display vector, with a protective antigen macrophage infectivity potentiator (MIP) of Chlamydia abortus (C. abortus), and its protective effect was evaluated in a mouse model. The MIP fusion protein accumulated at 1.2% of the ghost total protein mass and a significant portion of the protein was modified into lipoproteins upon translocation to the BG surface. Lipidated MIP-modified recombinant E. coli ghosts (rECG-lpp’-MIP) effectively promoted antigen-presenting cells (APCs) uptake of antigens and stimulated APCs activation in vivo and in vitro. Immunization with rECG-lpp’-MIP and no adjuvant induced intense specific humoral responses as well as Th1-biased cellular immune responses, which significantly improved the efficiency of C. abortus infection clearance in mice and reduced pathological damage to the uterus. In summary, this study demonstrates that recombinant E. coli ghosts modified with lipidated antigens could help to develop an effective C. abortus vaccine and aid in the development of a universal adjuvant-free vaccine platform.

Bisphenol A triggers activation of ocular immune system and aggravates allergic airway inflammation

Bisphenol A (BPA) is widely used in manufacturing plastic products, and it has been reported that exposure through the airway or orally aggravates allergic airway inflammation. Because BPA is detected in the atmosphere and indoor environments, the eyes can also be exposed to BPA. After ocular exposure to BPA and antigen via eye drops, we observed enhanced antigen uptake of antigen-presenting cells (APCs) in tear duct-associated lymphoid tissue (TALT). Additionally, we observed the formation of germinal center (GC) B cells in TALT and induction of allergic airway inflammation in mice sensitized with BPA and antigen via eye drops, followed by airway antigen exposure. We also found that DNAX-activating protein of 12 kDa (DAP12)-deficient mice displayed impaired activation of APCs enhanced by ocular exposure to BPA. These results indicate that ocular sensitization to BPA and allergen triggers allergic inflammation via TALT activation, and that DAP12 might be a key molecule for modulating the ocular immune system.

Abstract P182: Antigen Presenting Cell-specific Keap1-Nrf2 pathway Mediates Salt-Sensitive Hypertension in Humans

Background: Hypertension remains the leading cause of mortality worldwide and is a primary risk factor for cardiovascular disease. Of the 1.3 billion people globally affected by hypertension, over 50% exhibit salt-sensitivity of blood pressure (SSBP), which leads to higher rates of mortality, morbidity, and kidney damage compared to those with salt-resistant hypertension. Previously our research has shown that high salt intake activates antigen-presenting cells (APCs), causing inflammation and hypertension. This pro-inflammatory response is partly driven by the epithelial sodium channel (ENaC), which facilitates sodium ion transport into APCs. While the Keap1-Nrf2 pathway is known for its role in antioxidant defense and inflammatory responses, its contribution to salt-sensitive hypertension remains unclear. We hypothesize that ENaC-dependent sodium entry triggers inflammation and activates the Sp1-MALAT1-Keap1-Nrf2 signaling axis in APCs, thereby contributing to SSBP. Method: We utilized a well-established inpatient protocol to phenotype participants for salt sensitivity of blood pressure. Additionally, we conducted RNA sequencing (RNAseq) on human monocytes exposed to elevated sodium levels in vitro and performed Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) analysis on peripheral blood mononuclear cells (PBMCs). Results: We found that whereas high salt did not significantly increases expression of Sp1 (5380.63 ± 359.77 vs 7414.54 ± 434.19, q=0.829), MALAT1 (86888.54 ±12200.12 vs 219429.90 ± 109994.16, q=0.717), Keap1 (1586.54 ± 132.94 vs 2203.72 ± 177.48, q=0.884), it significantly increased Nrf2 expression (5080.36 ± 416.64 vs 5443.54 ± 432.78, q=0.019) in RNAseq analysis of human high salt compared to normal salt treated monocyte. Furthermore, the results of the CITE-seq experiment indicated that changes in the expression of the Sp1 correlate with SSBP (r=0.5205, p=0.038). Conclusion: These preliminary findings reveal a physiological link between inflammation and salt-sensitive hypertension through the Sp1-MALAT1-Keap1-Nrf2 signaling axis in APCs. The activation of APCs mediated by Sp1 could potentially serve as a diagnostic marker for salt sensitivity in blood pressure.

Eftilagimod Alpha (a Soluble LAG-3 Protein) Combined With Pembrolizumab in Second-Line Metastatic NSCLC Refractory to Anti–Programmed Cell Death Protein 1/Programmed Death-Ligand 1-Based Therapy: Final Results from a Phase 2 Study

IntroductionEftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4+ and CD8+) activation and helps overcome resistance to programmed cell death protein 1 or programmed cell death-ligand 1 (PD-(L)1) inhibitors. We assessed efti plus pembrolizumab in second-line anti–PD-(L)1-refractory metastatic patients with NSCLC. MethodsAfter confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary endpoint was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary endpoints included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory endpoints included tumor growth kinetics and predefined subgroup analyses. Programmed cell death-ligand 1 tumor proportion score was assessed centrally. ResultsThirty-six patients were enrolled from April 2019 to August 2021 using Simon’s two-stage design. Most patients (81.8%) had low or negative (<50%) PD-(L)1 tumor proportion score. First-line therapy was anti–PD-(L)1-based for all patients, combined with chemotherapy for 66.7%. The confirmed objective response and disease control rates were 8.3% and 33.3%. The median progression-free survival was 2.1 months and the median OS was 9.9 months. Patients exhibiting high PD-(L)1 expression or acquired resistance to PD-(L)1 inhibitors revealed superior response and survival outcomes, and OS was closely correlated with disease control. No treatment-emergent adverse event led to permanent discontinuation of study treatment. ConclusionsEfti plus pembrolizumab was well-tolerated and revealed signs of antitumor activity in patients with NSCLC resistant to PD-(L)1 inhibitors, warranting further investigation. Trial registration number: NCT03625323.

Nanoparticles targeting immune checkpoint protein VISTA induce potent antitumor immunity

BackgroundImmune checkpoint protein V-domain immunoglobulin suppressor of T cell activation (VISTA) controls antitumor immunity and is a valuable target for cancer immunotherapy. Previous mechanistic studies have indicated that VISTA impairs...

Modulation of antigen delivery and lymph node activation in non-human primates by saponin adjuvant SMNP.

Saponin-based vaccine adjuvants are potent in preclinical animal models and humans, but their mechanisms of action remain poorly understood. Here, using a stabilized HIV envelope trimer immunogen, we carried out studies in non-human primates (NHPs) comparing the most common clinical adjuvant alum with Saponin/MPLA Nanoparticles (SMNP), a novel ISCOMs-like adjuvant. SMNP elicited substantially stronger humoral immune responses than alum, including 7-fold higher peak antigen-specific germinal center B cell responses, 18-fold higher autologous neutralizing antibody titers, and higher levels of antigen-specific plasma and memory B cells. PET-CT imaging in live NHPs showed that, unlike alum, SMNP promoted rapid antigen accumulation in both proximal and distal lymph nodes (LNs). SMNP also induced strong type I interferon transcriptional signatures, expansion of innate immune cells, and increased antigen presenting cell activation in LNs. These findings indicate that SMNP promotes multiple facets of the early immune response relevant for enhanced immunity to vaccination.

High Cellular Internalization of Virus-Like Mesoporous Silica Nanoparticles Enhances Adaptive Antigen-Specific Immune Responses against Cancer.

Effective activation of an antigen-specific immune response hinges upon the intracellular delivery of cancer antigens to antigen-presenting cells (APCs), marking the initial stride in cancer vaccine development. Leveraging biomimetic topological morphology, we employed virus-like mesoporous silica nanoparticles (VMSNs) coloaded with antigens and toll-like receptor 9 (TLR9) agonists to craft a potent cancer vaccine. Our VMSNs could be efficiently internalized by APCs to a greater extent than their nonviral structured counterparts, thereby promoting the activation of APCs by upregulating the TLR9 pathway and cross-presenting ovalbumin (OVA) epitopes. In in vivo animal study, VMSN-based nanovaccines triggered substantial CD4+ and CD8+ lymphocyte populations in both lymph nodes and spleen while inducing the effector memory of adaptive T cells. Consequently, VMSN-based nanovaccines suppressed tumor progression and increased the survival rate of B16-OVA-bearing mice in both prophylactic and therapeutic studies. The combination of immune checkpoint blockade (ICB) with the VMSN-based nanovaccine has synergistic effects in significantly preventing tumor progression under therapeutic conditions. These findings highlight the potential of viral structure-mimicking mesoporous silica nanoparticles as promising candidates for antigen-delivering nanocarriers in vaccine development.

Spatiotemporal coordination of antigen presentation and co-stimulatory signal for enhanced anti-tumor vaccination

Controlled-release systems enhance anti-tumor effects by leveraging local antigen persistence for antigen-presenting cells (APCs) recruitment and T cell engagement. However, constant antigen presentation alone tends to induce dysfunction in tumor-specific CD8+ T cells, neglecting the synergistic effects of co-stimulatory signal. To address this, we developed a soft particle-stabilized emulsion (SPE) to deliver lipopeptides with controlled release profiles by adjusting their hydrophobic chain lengths: C6-SPE (fast release), C10-SPE (medium release), and C16-SPE (slow release). Following administration, C6-SPE release antigen rapidly, inducing early antigen presentation, whereas C16-SPE's slow-release delays antigen presentation. Both scenarios missed the critical window for coordinating with the expression of CD86, leading to either T cell apoptosis or suboptimal activation. In contrast, C10-SPE achieved a spatiotemporally synergetic effect of the MHC-I-peptide complex and co-stimulatory signal (CD86), leading to effective dendritic cell (DC) activation, enhanced T cell activation, and tumor regression in EG7-OVA bearing mice. Additionally, co-delivery of cytosine-phosphate-guanine (CpG) with SPE provided a sustained expression of the CD86 window for DC activation, improving the immune response and producing robust anti-tumor effects with C6-SPE comparable to C10-SPE. These findings highlight that synchronizing the spatiotemporal dynamics of antigen presentation and APC activation may confer an optimal strategy for enhanced vaccinations.

Modulating Elasticity of Liposome for Enhanced Cancer Immunotherapy.

Cancer immunotherapy has emerged as a promising approach to cancer treatment in recent years. The physical and chemical properties of nanocarriers are critical factors that regulate the immune activation of antigen-presenting cells (APCs) in the tumor microenvironment (TME). Herein, we extensively investigated the behavior of liposome nanoparticles (Lipo-NPs) with different elasticities, focusing on their interaction with immune cells and their transport mechanisms from tumors to tumor-draining lymph nodes (tdLNs). Successfully preparing Lipo-NPs with distinct elastic properties, their varied behaviors were observed, concerning immune cell interaction. Soft Lipo-NPs exhibited an affinity to cell membranes, while those with medium elasticity facilitated the cargo delivery to macrophages through membrane fusion. Conversely, hard Lipo-NPs enter macrophages via classical cellular uptake pathways. Additionally, it was noted that softer Lipo-NPs displayed superior transport to tdLNs in vivo, attributed to their deformable nature with lower elasticity. As a result, the medium elastic Lipo-NPs with agonists (cGAMP), by activating the STING pathway and enhancing transport to tdLNs, promoted abundant infiltration of tumor-infiltrating lymphocytes (TILs), leading to notable antitumor effects and extended survival in a melanoma mouse model. Furthermore, this study highlighted the potential synergistic effect of medium elasticity Lipo-NPs with immune checkpoint blockade (ICB) therapy in preventing tumor immune evasion. These findings hold promise for guiding immune-targeted delivery systems in cancer immunotherapy, particularly in vaccine design for tdLNs targeting and eradicating metastasis within tdLNs.

Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, is effective against tumors poorly responsive to conventional immunotherapy.

Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.

Evaluation of the adjuvant effect of imiquimod and CpG ODN 1826 in chimeric DNA vaccine against Japanese encephalitis

Vaccines represent a significant milestone in the history of human medical science and serve as the primary means for controlling infectious diseases. In recent years, the geographical distribution of Japanese encephalitis viruses (JEV) of various genotypes has become increasingly complex, which provides a rationale for the development of safer and more effective vaccines. The advent of subunit and nucleic acid vaccines, especially propelled by advancements in genetic engineering since the 1980s, has accelerated the application of novel adjuvants. These novel vaccine adjuvants have diversified into toll-like receptor (TLR) agonists, complex adjuvants, nanoparticles and so on. However, the efficacy of adjuvant combinations can vary depending on the host system, disease model, or vaccine formulation, sometimes resulting in competitive or counteractive effects. In our previous study, we constructed a pJME-LC3 chimeric DNA vaccine aimed at inducing an immune response through autophagy induction. Building on this, we investigated the impact of the TLR7/8 agonist imiquimod (IMQ) and the TLR9 agonist CpG ODN 1826 as adjuvants on the immunogenicity of the Japanese encephalitis chimeric DNA vaccine. Our findings indicate that the combination of the pJME-LC3 vaccine with IMQ and CpG ODN 1826 adjuvants enhanced the innate immune response, promoting the maturation and activation of antigen-presenting cells in the early immune response. Furthermore, it played a regulatory and optimizing role in subsequent antigen-specific immune responses, resulting in effective cellular and humoral immunity and providing prolonged immune protection. The synergistic effect of IMQ and CpG ODN 1826 as adjuvants offers a novel approach for the development of Japanese encephalitis nucleic acid vaccines.

Investigation of antigen-presenting cells in the intestinal mesentery in normal and adhesive processes

The morphology and topography of dendritic cells in the mesentery of the small intestine, their quantity, and their presence under normal conditions and during progressive adhesive processes have been insufficiently studied, presenting an important issue in immunomorphology. This study aimed to identify and determine the functional activity of antigen-presenting cells using lectin histochemistry with peanut and lentil lectins under normal conditions and during adhesive processes. The methods employed included morphometric analysis, lectin histochemistry, and statistical analysis. For the first time, using lectin histochemistry with lentil and soy lectins, functionally active and immunologically immature antigen-presenting cells were found in the structure of lymphoid clusters of the small intestine mesentery. A correlation was established between the progression of adhesion processes and the number of antigen-presenting cells. Correlation between dendritic cells and the quantity of immunologically immature lymphocytes and B-lymphocytes was identified, enhancing the understanding of the functional mechanisms of the local arm of innate immunity. An increasing trend in immunologically immature lymphocytes and B-lymphocytes was observed alongside an increase in antigen presenting cells. The results indicated that the activation of dendritic cells in mesenteric tissues induced an increase in immunologically immature lymphocytes, from which B-lymphocytes subsequently developed, initiating a local immune response. The increased frequency of PNA+- and LCA+- antigen-presenting cells pointed to an elevated immune reactivity of lymphoid clusters. This study on the distribution of antigen-presenting cells contributes to a deeper understanding of the structure of lymphoid tissue associated with serous membranes, as well as fat-associated lymphoid aggregates, and underscores the connection between innate and adaptive immunity in the abdominal cavity