In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.

Using Tetrahedral framework nucleic acids, we combined antigenic peptides to create the "DART" vaccine: DNA framework-Antigenic peptide-RNA modification-Targeting aptamer coupling. Generating antigen-specific tolerogenic dendritic cells (tolDCs), for systemic lupus erythematosus (SLE) is a potential therapeutic strategy for addressing compromised autoimmune tolerance. However, simple antigenic peptides degrade easily, lack specificity for delivery to dendritic cells (DCs), and cannot transform DCs to tolDCs. Therefore, this study aims to employ DART to generate tolDCs and compare DART-treated DCs to tolDCs. DART improved peptide stability, specifically targeted DCs, induced tolDCs in situ, and showed promising outcomes in mitigating SLE symptoms in the MRL/lpr mouse model. DART effectively normalized the plasma cytokine levels, glomerulonephritis, and joint lesions in MRL/lpr mice. These findings highlight the potential of the DART vaccine to induce transformation of DCs to tolDCs and address SLE symptoms, suggesting novel therapeutic utility. These findings may advance vaccine design for various autoimmune diseases.

Over the past few decades, there has been significant advancement in the field of tumor immunotherapy. For many years vaccination against infectious diseases have been available. On the other hand very few cancer vaccines have been approved for human use. Ideal Cancer vaccines are biological response modifier work by stimulating both humoral and cellular immunity while overcoming the immunological suppression found in tumor. Two types of cancer vaccine: Prophylactic and therapeutic cancer vaccines are recommended for clinical use of individuals. HPV and HBV vaccines are the two widely used preventive vaccine used for treatment of cervical and hepatocellular carcinoma respectively and are approved by Food and Drug Administration (FDA). In therapeutic vaccine only three are approved: Sipuleucel T-cell vaccine for treatment refractory prostatic cancer, BCG vaccine for early bladder cancer and T-VEC for inoperable melanoma. Active ingredient in all cancer vaccines is an antigen. Antigens used for formulating cancer vaccines along with adjuvants optimizes immunogenicity in it. Heterogeneity within and between cancer types, screening and identifying suitable antigen specific to tumors and selection of vaccine delivery platforms are challenges in the development of vaccines. Adoptive cell therapy, Chimeric antigen receptor T cell therapy are recent breakthrough for cancer treatment.

Cancer nanovaccines hold the promise for personalization, precision, and pliability by integrating all the elements essential for effective immune stimulation. An effective immune response requires communication and interplay between antigen-presenting cells (APCs), tumor cells, and immune cells to stimulate, extend, and differentiate antigen-specific and non-specific anti-tumor immune cells. The versatility of nanomedicine can be adapted to deliver both immunoadjuvant payloads and antigens from the key players in immunity (i.e., APCs and tumor cells). The imperative for novel cancer medicine is particularly pressing for less common but more devastating KIT-mutated acral and mucosal melanomas that are resistant to small molecule c-kit and immune checkpoint inhibitors. To overcome this challenge, we successfully engineered nanotechnology-enabled hybrid biomimetic nanovaccine (HBNV) comprised of membrane proteins (antigens to activate immunity and homing/targeting ligand to tumor microenvironment (TME) and lymphoid organs) from fused cells (of APCs and tumor cells) and immunoadjuvant. These HBNVs are efficiently internalized to the target cells, assisted in the maturation of APCs via antigens and adjuvant, activated the release of anti-tumor cytokines/inhibited the release of immunosuppressive cytokine, showed a homotypic effect on TME and lymph nodes, activated the anti-tumor immune cells/downregulated the immunosuppressive immune cells, reprogram the tumor microenvironment, and showed successful anti-tumor therapeutic and prophylactic effects.

Type 1 diabetes (T1D) is an organ-specific autoimmune disease caused by T cell-mediated pancreatic β cell destruction. To evaluate the effects of metformin on immune cells in autoimmune diabetes, we administered metformin intraperitoneally to two T1D mouse models and analyzed autoimmune diabetes progression. In a cyclophosphamide (CY)-induced T1D model in male non-obese diabetic (NOD) mice, intraperitoneal administration of metformin significantly prevented autoimmune diabetes. Treatment with metformin showed a decrease in activated T cells, CD44hiCD62Llo effector memory cells, macrophages, and dendritic cells (DCs), and an increase in CD44hiCD62Lhi central memory cells, B cells, and regulatory T cells (Tregs) in splenocytes. Interestingly, metformin treatment showed a decrease in activated T cells, CD4+ effector memory T cells and Th1-type antigen-specific cells in PLN cells. IL-17 production was significantly suppressed in metformin-treated mice. TNF-α production from DCs in vitro was dose-dependently suppressed by metformin. Activity of mTOR signaling was significantly reduced in CD4+ T cells, CD8+ T cells, and B220+ B cells. In addition, activities of mTOR and STAT3 signaling in DCs were also reduced significantly. Furthermore, metformin treatment in female NOD mice, a spontaneous T1D model, significantly suppressed autoimmune diabetes onset as well and an increase in Tregs was observed. Our results suggest that metformin may suppress autoimmunity and have therapeutic potential in T1D progression as an immunomodulator.

Although several traditional Chinese medicine formulas have demonstrated remarkable outcomes in suppressing the severe gastrointestinal toxicity induced by irinotecan (CPT-11), few studies have investigated whether enhanced anti-cancer efficacy and reduced intestinal toxicity can be achieved through co-administration. CPT-11, as a first-line drug for treating colorectal cancer, has the side effect of intestinal toxicity. Previous studies have primarily focused on using traditional Chinese medicine to alleviate diarrhea caused by CPT-11. The combination of the classic Chinese medicine prescription Gegen Qinlian decoction (GQD) extract and CPT-11 can significantly reduce its intestinal toxicity. However, the mechanism by which it enhances anti-cancer effects remains to be elucidated.

To investigate the combined effects of GQD and CPT-11 on colorectal cancer progression and intestinal toxicity.

The CT-26 xenograft tumor-bearing mouse model was established to evaluate the synergistic antitumor effects of GQD extract and CPT-11. Tumor size and tumor tissue changes were assessed, and flow cytometry was employed to analyze immune cell populations, thereby evaluating the impact of the combined treatment on tumor growth inhibition and immune modulation. Under anaerobic glycolysis conditions, glucose uptake and cell viability of CT26 cells were measured, and Western blotting analysis was used to determine the protein expression of PKM2 and GAPDH in tumors, assessing the metabolic impact of GQD extract on cancer cells. Flow cytometry was also used to assess the polarization of macrophages in colon tissue, and ELISA was employed to measure cytokine levels in colon tissue, evaluating the protective effect of GQD extract on the colon.

The combination of GQD extract and CPT-11 significantly increased tumor growth suppression and decreased intestinal toxicity in the mouse model. The anti-cancer synergy was reduced Treg cell immunosuppression and increased CD4+ and CD8+ T cell populations. GQD extract regulated glucose uptake and cell viability in CT-26 cells under anaerobic glycolysis, potentially disrupting cancer cell glycolysis. GQD also alleviated intestinal toxicity by modulating cytokine levels and promoting macrophage polarization from M1 to M2 in colon tissues.

The study indicates that GQD extract improves CPT-11 efficacy in treating colorectal cancer and provides insights into the synergistic effects of TCM formulas in cancer treatment.

Dendritic cell-based therapeutic tumor vaccines are an active immunotherapy that has been commonly tried in the clinic,traditional treatment modalities for malignant tumors, such as surgery, radiotherapy and chemotherapy, have the disadvantages of high recurrence rates and side effects. The dendritic cell vaccination destroys cells from tumors by means of the patient's own system of immunity, a very promising treatment. However, due to the suppression of the tumor immune microenvironment, the difficulty of screening for optimal specific antigens, and the high technical difficulty of vaccine production. Most tumor vaccines currently available in the clinic have failed to produce significant clinical therapeutic effects. In this review, the fundamentals of therapeutic dendritic cells vaccine therapy are briefly outlined, with a focus on the progress of therapeutic Dendritic cells vaccine research in the clinic and the initiatives undertaken to enhance dendritic cell vaccinations' anti-tumor effectiveness. It is believed that through the continuous exploration of novel therapeutic strategies, therapeutic dendritic cells vaccines can play a greater role in improving tumor treatment for tumor patients.

Strategies to improve the therapeutic efficacy of cancer immunotherapy with immune checkpoint inhibitors include targeting additional immunosuppressive compartments in the tumor microenvironment (TME). Inhibitory macrophages (Mφ) can be one of the most abundant immune cells in the TME associated with poor prognosis. However, to date, selective Mφ depletion strategies as a cancer immunotherapy have not been successful in clinical trials. Macrophage Receptor with Collagenous Structure (MARCO) is one of a family of class-A scavenger receptors expressed by Mφ in the TME and is one of the most upregulated transcripts in dendritic cells (DC) following their ex vivo uptake of dead tumor cells. The clinical significance of MARCO expression in the TME is not fully understood.

The therapeutic potential of targeting MARCO by an anti-murine MARCO (ED31, clone ED31) monoclonal antibody, which inhibits ligand-binding to MARCO, was explored in combination with anti-cytotoxic T-lymphocyte associated protein 4 (anti-CTLA-4) or anti-programmed cell death protein-1 (anti-PD-1) in C57BL/6J mice bearing B16F10 or Pan02 tumors. The mechanism by which ED31 impacts the TME was investigated by flow cytometry in the different treatment arms. The contribution of Mφ was assessed by both in vivo depletion and in vitro functional assays. Chemokine production was measured by a bead-based multiplex assay.

ED31 enhanced antitumor efficacy of anti-CTLA-4, but not of anti-PD-1. Analysis of the TME revealed that adding ED31 to anti-CTLA-4 substantially increased immune cell infiltration, including mature conventional DC recruitment, that was due to a switch to M1-pattern chemokines by Mφ. Mφ depletion completely abrogated both the increase in immune cell infiltration and chemokine production, and abolished the antitumor efficacy of the combination therapy.

Targeting MARCO as an additional checkpoint in the TME can offer a strategy to improve the antitumor efficacy of anti-CTLA-4 through a mechanism involving Mφ reprogramming rather than their depletion.

With the use of T cell receptor T cells (TCR-T cells) and chimeric antigen receptor T cells (CAR-T cells), T-cell immunotherapy for cancer has advanced significantly in recent years. CAR-T cell therapy has demonstrated extraordinary success when used to treat hematologic malignancies. Nevertheless, there are several barriers that prevent this achievement from being applied to solid tumors, such as challenges with tumor targeting and inadequate transit and adaption of genetically modified T-cells, especially in unfavorable tumor microenvironments The deficiencies of CAR-T cell therapy in the treatment of solid tumors are compensated for by TCR-T cells, which have a stronger homing ability to initiate intracellular commands, 90% of the proteins can be used as developmental targets, and they can recognize target antigens more broadly. As a result, TCR-T cells may be more effective in treating solid tumors. In this review, we discussed the structure of TCR-T and have outlined the drawbacks of TCR-T in cancer therapy, and suggested potential remedies. This review is crucial in understanding the current state and future potential of TCR-T cell therapy. We emphasize how important it is to use combinatorial approaches, combining new combinations of various emerging strategies with over-the-counter therapies designed for TCR-T, to increase the anti-tumor efficacy of TCR-T inside the TME and maximize treatment safety, especially when it comes to solid tumor immunotherapies.

Renal tumors with inferior vena cava tumor thrombus (IVCTT) remain a challenge in urology. However, in vivo models remain unavailable, which hampers the elucidation of its pathogenesis, identification of therapeutic targets, and screening for effective drugs. In this study, we initially develop two IVCTT models in BALB/c and BALB/c-nu/nu mice using the mouse Renca cell line. The pathological features and immune microenvironment of IVCTT in immunocompetent mice closely resembles those observed in humans. Single-cell transcriptome sequencing, immunohistochemistry and multiplex immunohistochemistry reveal a predominance of monocytes, macrophages, and neutrophils within IVCTT, mirroring the cellular composition of the human IVCTT; however, fewer lymphocytes are observed. The IVCTT in immunodeficient mice progresses much faster than in immunocompetent mice. More importantly, we successfully use the human tumor cell line on the BALB/c nu/nu mice to create an IVCTT model. The proposed in vivo models mimic the progression of renal tumors with IVCTT, clarify that the immune system can inhibit tumor thrombus progression, and provide tools for subsequent mechanistic research and translational preclinical studies.

The Transforming Growth Factor-beta (TGF-β) signaling pathway, with SMAD4 as its central mediator, plays a pivotal role in regulating cellular functions, including growth, differentiation, apoptosis, and immune responses. While extensive research has elucidated SMAD4's role in tumorigenesis, its functions within immune cells remain underexplored. This review synthesizes current knowledge on SMAD4's diverse roles in various immune cells such as T cells, B cells, dendritic cells, and macrophages, highlighting its impact on immune homeostasis and pathogen response. Understanding SMAD4's role in immune cells is crucial, as its dysregulation can lead to autoimmune disorders, chronic inflammation, and immune deficiencies. The review emphasizes the significance of SMAD4 in immune regulation, proposing that deeper investigation could reveal novel therapeutic targets for immune-mediated conditions. Insights into SMAD4's involvement in processes like T cell differentiation, B cell class switch recombination, and macrophage polarization underscore its potential as a therapeutic target for a range of diseases, including autoimmune disorders and cancer.

The perioperative period is crucial for determining postoperative tumor recurrence and metastasis. Various factors in postoperative lesions can diminish the therapeutic effect of conventional chemoradiotherapy, while emerging immunotherapy is restricted. The combination use of inflammatory inhibitors during treatment is also controversial. Here, a modular microneedle prepared from engineered keratin proteins is reported, which spatially and temporally differentiates the microenvironment of immune cell activation required for immunotherapy from that of wound healing. The recombinant keratin-84-T-based needle root layer, mainly retained in the epidermis, facilitated dendritic cell recruitment to achieve maximum antigen presentation of loaded vaccines. Meanwhile, the recombinant keratin-81-1Aα-based needle tip layer, located within the dermis, rapidly mitigated inflammatory responses while promoting tissue repair and regeneration. Unlike simply mixing immunotherapy and wound treatment, this spatiotemporal segmentation approach maximized the efficacy of immune therapeutics while promoting wound healing, making it suitable for application throughout the perioperative period.

Non-tuberculous Mycobacteria (NTM) are found extensively in various environments, yet most are non-pathogenic. Only a limited number of these organisms can cause various infections, including those affecting the lungs, skin, and central nervous system, particularly when the host's autoimmune function is compromised. Among these, Non-tuberculous Mycobacteria Pulmonary Diseases (NTM-PD) are the most prevalent. Currently, there is a lack of effective treatments and preventive measures for NTM infections. This article aims to deepen the comprehension of the pathogenic mechanisms linked to NTM and to formulate new intervention strategies by synthesizing current research and detailing the different tactics used by NTM to avoid elimination by the host's immune response. These intricate mechanisms not only affect the innate immune response but also successfully oppose the adaptive immune response, establishing persistent infections within the host. This includes effects on the functions of macrophages, neutrophils, dendritic cells, and T lymphocytes, as well as modulation of cytokine production. The article particularly emphasizes the survival strategies of NTM within macrophages, such as inhibiting phagosome maturation and acidification, resisting intracellular killing mechanisms, and interfering with autophagy and cell death pathways. This review aims to deepen the understanding of NTM's immune evasion mechanisms, thereby facilitating efforts to inhibit its proliferation and spread within the host, ultimately providing new methods and strategies for NTM-related treatments.

Plasmacytoid dendritic cells produce large amounts of type-I interferon (IFN-I) upon sensing nucleic acid components of pathogens by Toll-like receptors (TLR7 and TLR9). The transcription factor Spi-B has the DNA-binding Ets domain, and transactivates the Ifna4 promoter co-operatively with IFN regulatory factor-7 (IRF-7) for TLR7/TLR9-induced IFN-I production. Spi-B associates with IRF-7, and activates transcription by binding to the 5'-AGAA-3' sequence, being different from 5'-GGAA-3', known as the Ets domain recognition sequence. To understand the molecular mechanism for the co-operative transactivation of the Ifna4 promoter by Spi-B and IRF-7, we performed X-ray structural determination of the Spi-B Ets domain in complex with target DNAs, including 5'-AGAA-3' and 5'-GGAA-3' sequences. Furthermore, we conducted a modeling study of the complex of the Spi-B and IRF-7 with Ifna4 promoter DNA. X-ray structures showed that the binding of the Spi-B Ets domain induces a kink in DNA at the recognition sequence, and a more kinked DNA structure was observed in 5'-AGAA-3' than 5'-GGAA-3'. A modeling study showed that the Spi-B-induced kinked DNA structure in 5'-AGAA-3' is favorable for Spi-B and IRF-7 to approach each other for association on DNA.

Cancer vaccines are promising therapeutic approaches to enhance specific T-cell immunity against most solid tumors. By stimulating anti-tumor immunity, clearing minimal residual disease, and minimizing adverse effects, these vaccines target tumor cells and are effective when combined with immune checkpoint blockade or other immunotherapies. However, the development of tumor cell-based vaccines faces quality issues due to poor immunogenicity, tumor heterogeneity, a suppressive tumor immune microenvironment, and ineffective delivery methods. In contrast, extracellular vesicles (EVs), naturally released by cells, are considered the ideal drug carriers and vaccine platforms. EVs offer highly organ-specific targeting, induce broader and more effective immune responses, and demonstrate superior tissue delivery ability. The development of EV vaccines is crucial for advancing cancer immunotherapy. Compared to cell-based vaccines, EV vaccines produced under Good Manufacturing Practices (GMP) offer advantages such as high safety, ease of preservation and transport, and a wide range of sources. This review summarizes the latest research findings on EV vaccine and potential applications in this field. It also highlights novel neoantigens for the development of EV vaccines against cancer.

This study assesses the associations between dendritic cells, HPV 6 and 11, and Recurrent Respiratory Papillomatosis (RRP) aggressiveness.

The Derkay score was calculated using information obtained from the medical records. Biopsies from 36 patients with juvenile RRP (JRRP) and 43 adult RRP (ARRP) patients were analyzed under light microscopy, and their clinical data were collected. Immunohistochemical analysis using antibodies against CD83, CD1a, Factor XIIIa, and S100 was performed, and inflammatory cells were quantified. Data obtained were analyzed using the chi-squared test, in addition to the Mann-Whitney and Z tests for two proportions, considering a confidence interval of 95% and p < 0.05 as statistically significant.

A higher quantity of S100 was identified in the epithelium (p < 0.001) and in the conjunctive tissue (p = 0.027) among the ARRP cases, while CD83 (p = 0.025) and Factor XIIIa (p = 0.018), both in the epithelium, were identified among the JRRP cases. We observed significant association between a higher quantity of CD83 in the epithelium in the juvenile group with a low Derkay index (p = 0.034) and with HPV 6 (p = 0.039).

An increased quantity of dendritic cells is present in individuals diagnosed with RRP, regardless of age, and this may be related to the lower Derkay index, regardless of the HPV type detected.

Recent developments in biomimetic nanoparticles, specifically carbohydrate polymer-coated cell membrane nanoparticles, have demonstrated considerable promise in treating cancer. These systems improve drug delivery by imitating natural cell actions, enhancing biocompatibility, and decreasing immune clearance. Conventional drug delivery methods frequently face challenges with non-specific dispersal and immune detection, which can hinder their efficiency and safety. These biomimetic nanoparticles improve target specificity, retention times, and therapeutic efficiency by using biological components like chitosan, hyaluronic acid, and alginate. Chitosan-based nanoparticles, which come from polysaccharides found in nature, have self-assembly abilities that make them better drug carriers. Hyaluronic acid helps target tissues more effectively, especially in cancer environments where there are high levels of hyaluronic acid receptors. Alginate-based systems also enhance drug delivery by being biocompatible and degradable, making them ideal choices for advanced therapeutic uses. Moreover, these particles hold potential for overcoming resistance to multiple drugs and boosting the body's immune reaction to tumors through precise delivery and decreased side effects of chemotherapy drugs. This review delves into the possibilities of using carbohydrate polymer-functionalized nanoparticles and their impact on enhancing the efficacy of cancer treatment.

At this stage in the COVID-19 pandemic, most infections are "breakthrough" infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.

Tumor-draining lymph node dendritic cells (DCs) are poor stimulators of tumor antigen-specific CD4 T cells; however, the mechanism behind this defect is unclear. We now show that, in tumor-draining lymph node DCs, a large proportion of major histocompatibility complex class II (MHC-II) molecules retains the class II-associated invariant chain peptide (CLIP) fragment of the invariant chain bound to the MHC-II peptide binding groove due to reduced expression of the peptide editor H2-M and enhanced activity of the CLIP-generating proteinase cathepsin S. The net effect of this is that MHC-II molecules are unable to efficiently bind antigenic peptides. DCs in mice expressing a mutation in the invariant chain sequence that results in enhanced MHC-II-CLIP accumulation are poor stimulators of CD4 T cells and have diminished anti-tumor responses. Our data reveal a previously unknown mechanism of immune evasion in which enhanced expression of MHC-II-CLIP complexes on tumor-draining lymph node DCs limits MHC-II availability for tumor peptides.

The aim of this study was to improve the efficacy of Hepatitis B surface antigen (HBsAg) vaccination via liposome-loaded dissolvable microneedle (Lipo-dMN) patches. HBsAg liposomes were prepared using the thin-film hydration method and subsequently incorporated into dissolvable microneedle patches via a pre-vacuum approach. Liposomes, dissolvable microneedle patches (dMN), and Lipo-dMN were characterized for encapsulation efficiency, mechanical properties, morphology, skin insertion, in vitro release, cellular uptake, and in vivo vaccination studies. The HBsAg was encapsulated into liposomes with encapsulation efficiencies around 50 %, particle size around 160 nm, and zeta potential around -20 mV. HBsAg can maintain its activity during the preparation of dMN and Lipo-dMN. The intact pyramid microneedle has a sharp end and strong mechanical properties that allow easy insertion into the ex vivo pig skin. The dMN and Lipo-dMN, with a mechanical property of 1.6 N, readily penetrate the epidermis and release the HBsAg and HBsAg liposome to modulate the immune response. A comprehensive comparison of HBsAg subcutaneous injection and intradermal delivery of HBsAg and HBsAg liposome by dMN revealed different levels of anti-HBsAg IgG antibody. Inoculation with dMN and Lipo-dMN resulted in significantly higher levels of anti-HBsAg IgG antibodies (p < 0.01) compared to subcutaneous injection of HBsAg. In addition, we found that IgG levels increased significantly (P < 0.05) with increased dose of subcutaneous injection of HBsAg and intradermal delivery of dMN, but the opposite effect was observed in Lipo-dMN. The possible mechanism for this observation may be the increased cellular uptake of liposomes by BMDCs upon long-term incubation. In summary, this study presents a promising approach to enhance HBsAg vaccination efficacy through the synergistic combination of liposomes and dissolvable microneedles at reduced vaccine doses.

Esophageal cancer (EC) is the seventh-most prevalent cancer worldwide and is a significant contributor to cancer-related mortality. Metabolic reprogramming in tumors frequently coincides with aberrant immune function alterations, and extensive research has demonstrated that perturbations in energy metabolism within the tumor microenvironment influence the occurrence and progression of esophageal cancer. Current treatment modalities for esophageal cancer primarily include encompass chemotherapy and a limited array of targeted therapies, which are hampered by toxicity and drug resistance issues. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway, has exhibited promising results; however, a substantial proportion of patients remain unresponsive. The optimization of these immunotherapies requires further investigation. Mounting evidence underscores the importance of modulating metabolic traits within the tumor microenvironment (TME) to augment anti-tumor immunotherapy.

We selected relevant studies on the metabolism of the esophageal cancer tumor microenvironment and immune cells based on our searches of MEDLINE and PubMed, focusing on screening experimental articles and reviews related to glucose metabolism, amino acid metabolism, and lipid metabolism, as well their interactions with tumor cells and immune cells, published within the last five years. We analyzed and discussed these studies, while also expressing our own insights and opinions.

A total of 137 articles were included in the review: 21 articles focused on the tumor microenvironment of esophageal cancer, 33 delved into research related to glucose metabolism and tumor immunology, 30 introduced amino acid metabolism and immune responses, and 17 focused on the relationship between lipid metabolism in the tumor microenvironment and both tumor cells and immune cells.

This article delves into metabolic reprogramming and immune alterations within the TME of EC, systematically synthesizes the metabolic characteristics of the TME, dissects the interactions between tumor and immune cells, and consolidates and harnesses pertinent immunotherapy targets, with the goal of enhancing anti-tumor immunotherapy for esophageal cancer and thereby offering insights into the development of novel therapeutic strategies.

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen and progesterone receptors, and lack of human epidermal growth factor receptor 2 (HER2) expression. Traditional Chinese medicine (TCM) has demonstrated promising efficacy in treating TNBC. This study explored the mechanisms of pachymic acid (PA) on TNBC by merging network pharmacology with experimental validation. We acquired Microarray data of TNBC from the Gene Expression Omnibus (GEO). The related targets of PA were predicted and screened using the following 6 databases: Swiss Target Prediction, HERB (Herbal Medicine Database), ETCM (Encyclopedia of Traditional Chinese Medicine), BATMAN (Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine), HIT (Herb Ingredients' Targets Database), and PharmMapper. The STRING interaction network analysis tool was used to create Protein-Protein Interaction (PPI) networks. Enrichment analysis included Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). We conducted a pan-cancer analysis, tumor immune microenvironment analysis, and molecular docking. We performed cell experimental, included cytotoxicity assay, apoptosis analysis, proliferation assay, and migration and invasion assays. PA has potential for treating TNBC with the target of TOP2A, and platinum drug resistance possibly serving as the KEGG pathway through which PA exerts its therapeutic effects. PA is involved in processes such as nuclear division, chromosome segregation, mitotic nuclear division, condensed chromosome formation, and protein C-terminus binding. PA probably exert its therapeutic effects through the tumor immune microenvironment, involving elements such as Dendritic cells activated, Eosinophils, Macrophages M0, Macrophages M1, and T cells CD4 memory activated. The therapeutic effects of PA may vary across different subtypes of TNBC such as TNBC-BL1, TNBC-Metaplastic, and TNBC-BL2. This study provides compelling evidence that PA holds significant promise as a therapeutic agent for TNBC, primarily through its action on TOP2A and its influence on the TNBC.

In recent years, increased numbers of severe Streptococcus dysgalactiae subsp. equisimilis (SDSE) infections, including necrotizing soft tissue infections (NSTIs), have been reported. One of the main virulence factors of SDSE is streptokinase (Ska). Ska promotes bacterial spread in the tissue through Ska-plasminogen interactions and subsequent activation of plasminogen to plasmin. In this study, the impact of streptokinase on SDSE infections of human monocyte-derived dendritic cells (moDCs) was investigated. MoDCs were infected with SDSE strain S118 and its isogenic mutant lacking streptokinase. All infections were performed with and without human serum to compare direct Ska-mediated as well as plasmin activity-related effects. Intracellular killing kinetics, moDC viability and maturation, as well as the release of pro-inflammatory cytokines were assessed. Irrespective of the strain and experimental conditions, the bacteria were equally phagocytosed and killed. MoDCs remained viable, readily matured and secreted equal amounts of cytokines in response to S118 as well as S118Δska infections. Our data demonstrate that moDCs response to SDSE infections is not affected by Ska or its respective plasminogen activating function.

Synthetic long peptides (SLPs) are a promising vaccine modality that exploit dendritic cells (DC) to treat chronic infections or cancer. Currently, the design of SLPs relies on in silico prediction and multifactorial T cells assays to determine which SLPs are best cross-presented on DC human leukocyte antigen class I (HLA-I). Furthermore, it is unknown how TLR ligand-based adjuvants affect DC cross-presentation. Here, we generated a unique, high-quality immunopeptidome dataset of human DCs pulsed with 12 hepatitis B virus (HBV)-based SLPs combined with either a TLR1/2 (Amplivant®) or TLR3 (PolyI:C) ligand. The obtained immunopeptidome reflected adjuvant-induced differences, but no differences in cross-presentation of SLPs. We uncovered dominant (cross-)presentation on B-alleles, and identified 33 unique SLP-derived HLA-I peptides, several of which were not in silico predicted and some were consistently found across donors. Our work puts forward DC immunopeptidomics as a valuable tool for therapeutic vaccine design.

Lymph node (LN) targeting and antigen presentation by antigen-presenting cells (APCs) are critical factors affecting the immune responses induced by tumor vaccines. Autophagy activation promotes MHC class I and II antigen presentation in APCs. To enhance antigen presentation in LNs, we developed an aluminum hydroxide nanovaccine that simultaneously incorporates the autophagy-activating peptide Beclin-1 and the antigenic protein OVA (B/O@AN nanovaccine) through layer-by-layer electrostatic interaction. B/O@AN has a particle size of approximately 80 nm and efficiently targets lymph nodes following subcutaneous administration. The combination of the Beclin-1 peptide with the aluminum hydroxide nanovaccine promotes dendritic cell (DC) maturation. More importantly, B/O@AN facilitates antigen cross-presentation by promoting lysosomal escape and autophagy induction. After immunization, compared to O/@AN without Beclin-1, B/O@AN significantly augments antigen-specific cellular immune responses, leading to substantial increases in cytotoxic T lymphocytes (CTLs), T-helper 1 (Th1) cells, as well as serum antibody levels, thereby impeding melanoma development and progression in both prophylactic and therapeutic settings. These results provide evidence that autophagy activation strengthens antigen presentation and augments the antigen-specific immune responses of the aluminum hydroxide nanovaccine.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine playing a pivotal role during inflammation and immune responses. In the recent years, the function of IL-6 in the tumor microenvironment (TME) for affecting tumorigenesis and immunotherapy response has been investigated. The genetic mutations are mainly responsible for the development of cancer, while interactions in TME are also important, involving both cancers and non-cancerous cells. IL-6 plays a significant role in these interactions, enhancing the proliferation, survival and metastasis of tumor cells through inflammatory pathways, highlighting its carcinogenic function. Multiple immune cells including macrophages, T cells, myeloid-derived suppressor cells, dendritic cells and natural killer cells can be affected by IL-6 to develop immunosuppressive TME. IL-6 can also participate in the immune evasion through increasing levels of PD-L1, compromising the efficacy of therapeutics. Notably, IL-6 exerts a double-edge sword function and it can dually increase or decrease cancer immunotherapy, providing a challenge for targeting this cytokine in cancer therapy. Highlighting the complicated function of IL-6 in TME can lead to the development of effective therapeutics for cancer immunity.

Chitosan, a biodegradable and biocompatible natural polymer composed of β-(1-4)-linked N-acetyl glucosamine (GlcNAc) and d-glucosamine (GlcN) and derived from crustacean shells, has been widely studied for various biomedical applications, including drug delivery, cartilage repair, wound healing, and tissue engineering, because of its unique physicochemical properties. One of the most promising areas of research is the investigation of the immunomodulatory properties of chitosan, since the biopolymer has been shown to modulate the maturation, activation, cytokine production, and polarization of dendritic cells and macrophages, two key immune cells involved in the initiation and regulation of innate and adaptive immune responses, leading to enhanced immune responses. Several signaling pathways, including the cGAS-STING, STAT-1, and NLRP3 inflammasomes, are involved in chitosan-induced immunomodulation. This review provides a comprehensive overview of the current understanding of the in vitro immunomodulatory effects of chitosan. This information may facilitate the development of chitosan-based therapies and vaccine adjuvants for various immune-related diseases.

The mucosal immune system, as the most extensive peripheral immune network, serves as the frontline defense against a myriad of microbial and dietary antigens. It is crucial in preventing pathogen invasion and establishing immune tolerance. A comprehensive understanding of mucosal immunity is essential for developing treatments that can effectively target diseases at their entry points, thereby minimizing the overall impact on the body. Despite its importance, our knowledge of mucosal immunity remains incomplete, necessitating further research. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has underscored the critical role of mucosal immunity in disease prevention and treatment. This systematic review focuses on the dynamic interactions between mucosa-associated lymphoid structures and related diseases. We delve into the basic structures and functions of these lymphoid tissues during disease processes and explore the intricate regulatory networks and mechanisms involved. Additionally, we summarize novel therapies and clinical research advances in the prevention of mucosal immunity-related diseases. The review also addresses the challenges in developing mucosal vaccines, which aim to induce specific immune responses while maintaining tolerance to non-pathogenic microbes. Innovative therapies, such as nanoparticle vaccines and inhalable antibodies, show promise in enhancing mucosal immunity and offer potential for improved disease prevention and treatment.

Second-line treatment options for persistent, recurrent or metastatic (r/m) cervical cancer are limited. We investigated the safety, efficacy, and immunogenicity of the therapeutic DNA-based vaccine VB10.16 combined with the immune checkpoint inhibitor atezolizumab in patients with human papillomavirus (HPV)16-positive r/m cervical cancer.

This multicenter, single-arm, phase 2a study (NCT04405349, registered 26 May 2020) enrolled adult patients with persistent, r/m HPV16-positive cervical cancer. Patients received 3 mg VB10.16 (every 3 weeks (Q3W) for 12 weeks, hereafter every 6 weeks) combined with 1,200 mg atezolizumab (Q3W) for 48 weeks in total with a 12-month follow-up. The primary endpoints were incidence and severity of adverse events (AEs) and objective response rate (ORR; Response Evaluation Criteria in Solid Tumor V.1.1). ORR was assessed in the efficacy population, being all response-evaluable patients who received any administration of VB10.16 and atezolizumab and had at least one post-baseline imaging assessment.

Between June 16, 2020, and January 25, 2022, 52 patients received at least one administration of study treatment. Of these, 47 patients had a minimum of one post-baseline tumor assessment. The median follow-up time for survival was 11.7 months. AEs related to VB10.16 were non-serious and mainly mild injection site reactions (9 of 52 patients). There were no signs of new toxicities other than what was already described with atezolizumab. ORR was 19.1% (95% CI 9.1% to 33.3%). Median duration of response was not reached (n.r.) (95% CI 2.2 to n.r.), median progression-free survival was 4.1 months (95% CI 2.1 to 6.2), and median overall survival was 21.3 months (95% CI 8.5 to n.r.). In programmed death-ligand 1 (PD-L1)-positive patients (n=24), ORR was 29.2% (95% CI 12.6 to 51.1). HPV16-specific T-cell responses were analyzed in 36 of 47 patients with an increase observed in 22/36 (61%).

The therapeutic DNA-based vaccine VB10.16 combined with atezolizumab was safe and well tolerated showing a promising clinically meaningful efficacy with durable responses in patients with persistent, r/m HPV16-positive cervical cancer, especially if PD-L1-positive.

Recurrent spontaneous seizures with an extended epileptic discharge are the hallmarks of epilepsy. At present, there are several available anti-epileptic drugs (AEDs) in the market. Still no adequate treatment for epilepsy treatment is available. The main disadvantages of AEDs are their associated adverse effects. It is a challenge to develop new therapies that can reduce seizures by modulating the underlying mechanisms with no adverse effects. In the last decade, the neuromodulatory potential of phytoconstituents has sparked their usage in the treatment of central nervous system disorders. Curcumin is an active polyphenolic component that interacts at cellular and molecular levels. Curcumin's neuroprotective properties have been discovered in recent preclinical and clinical studies due to its immunomodulatory effects. Curcumin has the propensity to modulate signaling pathways involved in cell survival and manage oxidative stress, apoptosis, and inflammatory mechanisms. Further, curcumin can persuade epigenetic alterations, including histone modifications (acetylation/deacetylation), which are the changes responsible for the altered expression of genes facilitating the process of epileptogenesis. The bioavailability of curcumin in the brain is a concern that needs to be tackled. Therefore, nanonization has emerged as a novel drug delivery system to enhance the pharmacokinetics of curcumin. In the present review, we reviewed curcumin's modulatory effects on potential biomarkers involved in epileptogenesis including dendritic cells, T cell subsets, cytokines, chemokines, apoptosis mediators, antioxidant mechanisms, and cognition impairment. Also, we have discussed the nanocarrier systems for encapsulating curcumin, offering a promising approach to enhance bioavailability of curcumin.

Lung adenocarcinoma (LUAD) exhibits molecular heterogeneity, with mitochondrial damage affecting progression. The relationship between mitochondrial damage and immune infiltration, and Weighted Gene Co-expression Network Analysis (WGCNA)-derived biomarkers for LUAD classification and prognosis, remains unexplored.

The objective of our research is to identify gene modules closely related to the clinical stages of LUAD using the WGCNA method. Based on the genes within these modules, we constructed machine learning (ML) models for classification and prognosis prediction, thereby facilitating precise diagnosis and personalized treatment of LUAD.

Using GeneCards and The Cancer Genome Atlas (TCGA) databases, we screened differentially expressed mitochondrial damage-related genes in LUAD. Immune cell infiltration patterns were assessed using Single-Sample Gene Set Enrichment Analysis (SSGSEA) method. Functional enrichment analyses were conducted to explore biological functions and signaling pathways. Gene modules related to clinical stages of LUAD were identified by WGCNA. ML models were constructed for classification and prognosis prediction, and validated in an independent Gene Expression Omnibus (GEO) dataset.

The study revealed a significant relationship between mitochondrial damage and immune infiltration in LUAD. We identified a gene module closely associated with the clinical stages of LUAD. The ML models for classification and prognosis that were constructed demonstrated good effectiveness and generalization capabilities.

Mitochondrial damage-related genes are crucial in LUAD progression and linked to immune infiltration. The gene module and models identified have potential applications in LUAD classification and prognosis, offering novel markers for precision medicine.

This study uncovers the relationship between mitochondrial damage and immune infiltration in LUAD, paving the way for molecular classification, prognosis prediction, and personalized treatment strategies.

This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs, and various nonlymphoid tissues. Within this article, detailed protocols are presented that allow for the generation of single-cell suspensions from human nonlymphoid tissues including lung, skin, gingiva, intestine as well as from tumors and tumor-draining lymph nodes with a subsequent analysis of dendritic cells by flow cytometry. Further, prepared single-cell suspensions can be subjected to other applications including cellular enrichment procedures, RNA sequencing, functional assays, etc. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.

Several nutrients are crucial in enhancing the immune system and preserving the structural integrity of bodily tissue barriers. Vitamin D (VD) and zinc (Zn) have received considerable interest due to their immunomodulatory properties and ability to enhance the body's immune defenses. Due to their antiviral, anti-inflammatory, antioxidative, and immunomodulatory properties, the two nutritional powerhouses VD and Zn are crucial for innate and adaptive immunity. As observed with COVID-19, deficiencies in these micronutrients impair immune responses, increasing susceptibility to viral infections and severe disease. Ensuring an adequate intake of VD and Zn emerges as a promising strategy for fortifying the immune system. Ongoing clinical trials are actively investigating their potential therapeutic advantages. Beyond the immediate context of the pandemic, these micronutrients offer valuable tools for enhancing immunity and overall well-being, especially in the face of future viral threats. This analysis emphasizes the enduring significance of VD and Zn as both treatment and preventive measures against potential viral challenges beyond the current health crisis. The overview delves into the immunomodulatory potential of VD and Zn in combating viral infections, with particular attention to their effects on animals. It provides a comprehensive summary of current research findings regarding their individual and synergistic impacts on immune function, underlining their potential in treating and preventing viral infections. Overall, this overview underscores the need for further research to understand how VD and Zn can modulate the immune response in combatting viral diseases in animals.

Intestinal epithelial cells (IECs) and innate immune cells in the gastrointestinal tract (GIT) of chickens play crucial roles in pathogens defense and maintaining gut health. However, their effectiveness influenced with their developmental and functional stages during pre and post hatch periods of chick. During embryonic development, differentiation and migration of these innate immune systems are tightly regulated by diverse cellular and molecular factors. The maturation and functionality of IECs are histologically evident starting embryonic day (ED) 14. Moreover, the innate immun cells, such as dendritic cells (DCs), macrophages, natural killer (NK) cells, and gamma-delta (γδ) T cells have showed developmental expression varation, while most identified by the 3rd days of incubation and capable of responsing to their cognate ligands of pathogens by ED 17, it may not efficient during posthatch period. In modern poultry production, in ovo feeding of bioactive substances is a topic of interest to maximize the protection capability of hatched chicks by enhancing improvement on the development of innate immune systems. However, their actions and effects on each distinct innate immune involved response are inconsistent and not clearly understood. Thus, summarizing the ontogeny and function of IECs, innate immunity systems, and interaction mechanisms of in ovo feeding of bioactive substances could provide baseline information for designing targeted in ovo feeding interventions to modulate cell waise specific innate immune systems.

Platelets are non-nucleated mammalian cells originating from the cytoplasmic expulsion of the megakaryocytes. Megakaryocytes develop during hematopoiesis through megakaryopoiesis, whereas platelets develop from megakaryocytes through thrombopoiesis. Since their first discovery, platelets have been studied as critical cells controlling hemostasis or blood coagulation. However, coagulation and innate immune response are evolutionarily linked processes. Therefore, it has become critical to investigate the immunological functions of platelets to maintain immune homeostasis. Advances in immunology and platelet biology research have explored different critical roles of platelets, including phagocytosis, release of different immune mediators, and controlling functions of different immune cells by direct interaction and immune mediators. The current article discusses platelet's development and their critical role as innate immune cells, which express different pattern recognition receptors (PRRs), recognizing different pathogen or microbe-associated molecular patterns (PAMPs or MAMPs) and death/damage-associated molecular patterns (DAMPs) and their direct interactions with innate and adaptive immune cells to maintain immune homeostasis.

The use of peptides for cancer immunotherapy is a promising and emerging approach that is being intensively explored worldwide. One such peptide, GK-1, has been shown to delay the growth of triple-negative breast tumors in mice, reduce their metastatic capacity, and reverse the intratumor immunosuppression that characterizes this model. Herein, it is demonstrated that GK-1 is taken up by bone marrow dendritic cells in a dose-dependent manner 15 min after exposure, more efficiently at 37 °C than at 4 °C, implying an entrance into the cells by energy-independent and -dependent processes through clathrin-mediated endocytosis. Theoretical predictions support the binding of GK-1 to the hydrophobic pocket of MD2, preventing it from bridging TLR4, thereby promoting receptor dimerization and cell activation. GK-1 can effectively activate cells via a TLR4-dependent pathway based on in vitro studies using HEK293 and HEK293-TLR4-MD2 cells and in vivo using C3H/HeJ mice (hyporesponsive to LPS). In conclusion, GK-1 enters the cells by passive diffusion and by activation of the transmembrane Toll-like receptor 4 triggering cell activation, which could be involved in the GK-1 antitumor properties.

Nanoparticles can exert immune modulating effects in a host depending on composition, mode of administration, and type of disease. Although the specific mechanisms of nanoparticle-induced immune responses remain unclear, their uptake by macrophages and other phagocytic innate immune cells is considered to be a key event. Our objective here was to ascertain if nanoparticle-mediated activation of dendritic cells (DCs) occurs in vitro or in vivo when exposed to hydroxyethyl starch-coated iron oxide nanoparticles. For the present studies, our choice of nanoparticles, animal model, and experimental design is motivated by our previously published observations that systemic exposure can induce antitumor adaptive immune responses in mouse models of metastatic breast cancer. Here, we began by assessing the potential toxicity of systemic exposure to commercially available starch-coated Bionized Nanoferrite® nanoparticles (BP) by measuring body weight, complete blood count, and enzyme parameters in healthy FVB/NJ mice after repeated BP dosing. We observed no evidence of toxicity at doses up to 25 mg Fe per mouse, five-fold higher than those used in subsequent in vivo experiments. We then measured the expression of surface maturation markers (CD86, MHC II) in DCs incubated with BP in vitro. Although DCs cultured with BP revealed high levels of nanoparticle uptake, neither JAWSII dendritic cells nor bone marrow derived dendritic cells (BMDCs) showed significant changes in marker expression to indicate stimulation of maturation and effector function. To assess whether BP interactions in vivo produced different effects, we analyzed CD80, CD86, and MHC II expression of DCs recovered from the livers, spleens, bone marrows, and lymph nodes of mice injected once with BP (5 mg Fe). Interestingly, only DCs in spleens and bone marrow cells responded to BP exposure. DCs recovered from other organs showed no evidence of increased activation. These findings highlight complex interactions between living systems and nanoparticles, and their potential to mediate context-specific and selective activation of innate immune cells. Our study also emphasizes that results obtained from in vitro experiments must be interpreted with caution, as they may not faithfully represent responses in living systems.