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Biomedicine & Pharmacotherapy =... Aug 2023Traditionally, vaccines have helped eradication of several infectious diseases and also saved millions of lives in the human history. Those prophylactic vaccines have... (Review)
Review
Traditionally, vaccines have helped eradication of several infectious diseases and also saved millions of lives in the human history. Those prophylactic vaccines have acted through inducing immune responses against a live attenuated, killed organism or antigenic subunits to protect the recipient against a real infection caused by the pathogenic microorganism. Nevertheless, development of anticancer vaccines as valuable targets in human health has faced challenges and requires further optimizations. Dendritic cells (DCs) are the most potent antigen presenting cells (APCs) that play essential roles in tumor immunotherapies through induction of CD8 T cell immunity. Accordingly, various strategies have been tested to employ DCs as therapeutic vaccines for exploiting their activity against tumor cells. Application of whole tumor cells or purified/recombinant antigen peptides are the most common approaches for pulsing DCs, which then are injected back into the patients. Although some hopeful results are reported for a number of DC vaccines tested in animal and clinical trials of cancer patients, such approaches are still inefficient and require optimization. Failure of DC vaccination is postulated due to immunosuppressive tumor microenvironment (TME), overexpression of checkpoint proteins, suboptimal avidity of tumor-associated antigen (TAA)-specific T lymphocytes, and lack of appropriate adjuvants. In this review, we have an overview of the current experiments and trials evaluated the anticancer efficacy of DC vaccination as well as focusing on strategies to improve their potential including combination therapy with immune checkpoint inhibitors (ICIs).
Topics: Animals; Humans; Antigens, Neoplasm; Cancer Vaccines; CD8-Positive T-Lymphocytes; Dendritic Cells; Neoplasms; Tumor Microenvironment; Vaccination
PubMed: 37257227
DOI: 10.1016/j.biopha.2023.114954 -
Clinical Immunology (Orlando, Fla.) Oct 2023Systemic autoimmune diseases are characterized by increased production of type I interferon (IFN-1) and upregulation of IFN-1-inducible genes, suggesting an important... (Review)
Review
Systemic autoimmune diseases are characterized by increased production of type I interferon (IFN-1) and upregulation of IFN-1-inducible genes, suggesting an important role of the IFN-1 pathway in their pathogenesis. Recent studies have demonstrated increased IFN-1 expression in both primary and secondary antiphospholipid syndrome (APS), along with increased toll-like receptor type 9 activity and plasmacytoid dendritic cell function. The increasing knowledge of the association between IFN-1 and APS pathology may provide a rationale for conducting clinical trials to assess the efficacy of IFN-1-targeting drugs in reducing APS-related complications. In this narrative review, we summarize the current knowledge on the role of IFN-1 in APS pathogenesis, explore its clinical implications, and examine the existing evidence regarding therapeutic options that have been investigated to date.
Topics: Humans; Antiphospholipid Syndrome; Interferon Type I; Up-Regulation; Dendritic Cells; Interferons
PubMed: 37678720
DOI: 10.1016/j.clim.2023.109754 -
Human Vaccines & Immunotherapeutics Dec 2023A promising personal immunotherapy is autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from self-renewing autologous cancer cells....
A promising personal immunotherapy is autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) derived from self-renewing autologous cancer cells. DC-ATA are suspended in granulocyte-macrophage colony stimulating factor at the time of each subcutaneous injection. Previously, irradiated autologous tumor cell vaccines have produced encouraging results in 150 cancer patients, but the DC-ATA vaccine demonstrated superiority in single-arm and randomized trials in metastatic melanoma. DC-ATA have been injected into more than 200 patients with melanoma, glioblastoma, and ovarian, hepatocellular, and renal cell cancers. Key observations include: [1] greater than 95% success rates for tumor cell cultures and monocyte collection for dendritic cell production; [2] injections are well-tolerated; [3] the immune response is rapid and includes primarily TH1/TH17 cellular responses; [4] efficacy has been suggested by delayed but durable complete tumor regressions in patients with measurable disease, by progression-free survival in glioblastoma, and by overall survival in melanoma.
Topics: Humans; Cancer Vaccines; Glioblastoma; Melanoma; Antigens, Neoplasm; Kidney Neoplasms; Dendritic Cells
PubMed: 37133853
DOI: 10.1080/21645515.2023.2198467 -
Frontiers in Immunology 2023Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and treatment resistant cancers. Due to its desmoplastic and hypoxic nature along with an abundance of...
INTRODUCTION
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and treatment resistant cancers. Due to its desmoplastic and hypoxic nature along with an abundance of myeloid cell infiltration and scarce T cell infiltration, PDAC is considered a cold tumor.
METHODS
Here we sought to investigate myeloid cell infiltration and composition in PDAC spheroids by targeting the hypoxia-associated pathways endoplasmic reticulum oxidoreductase 1 alpha (ERO1a) and indoleamine 2,3-dioxygenase 1 (IDO1). Using MiaPaCa2 spheroids with hypoxic core, we assessed the roles of ERO1a and IDO1 inhibition in modulating monocyte infiltration and differentiation, followed by characterizing immunomodulatory factors secreted using LC-MS/MS.
RESULTS
Inhibition of ERO1a and IDO1 significantly improved monocyte infiltration and differentiation into dendritic cells. LC-MS/MS analysis of the PDAC spheroid secretome identified downregulation of hypoxia and PDAC pathways, and upregulation of antigen presentation pathways upon inhibition of ERO1a and IDO1. Furthermore, immunomodulatory factors involved in immune infiltration and migration including interleukin-8, lymphocyte cytosolic protein 1, and transgelin-2, were upregulated upon inhibition of ERO1a and IDO1.
DISCUSSION
Collectively, our results show that inhibition of ERO1a and IDO1 modulates the tumor microenvironment associated with improved monocyte infiltration and differentiation into dendritic cells to potentially influence therapeutic responses in patients with PDAC.
Topics: Humans; Chromatography, Liquid; Tandem Mass Spectrometry; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Hypoxia; Dendritic Cells; Tumor Microenvironment
PubMed: 38187398
DOI: 10.3389/fimmu.2023.1264012 -
Journal of Nanobiotechnology Sep 2023Cancer therapeutic vaccine can induce antigen-specific immune response, which has shown great potential in cancer immunotherapy. As the key factor of vaccine, antigen...
Cancer therapeutic vaccine can induce antigen-specific immune response, which has shown great potential in cancer immunotherapy. As the key factor of vaccine, antigen plays a central role in eliciting antitumor immunity. However, the insufficient antigen delivery and low efficiency of antigen presentation by dendritic cells (DCs) have greatly restricted the therapeutic efficiency of vaccine. Here we developed a kind of DC hybrid zinc phosphate nanoparticles to co-deliver antigenic peptide and photosensitive melanin. Owing to the chelating ability of Zn, the nanoparticles can co-encapsulate antigenic peptide and melanin with high efficiency. The nanovaccine showed good physiological stability with the hydration particle size was approximately 30 nm, and zeta potential was around - 10 mV. The nanovaccine showed homologous targeting effect to DCs in vivo and in vitro, efficiently delivering antigen to DCs. Meanwhile, the nanovaccine could effectively reflux to the tumor-draining lymph nodes. When combined with near-infrared irradiation, the nanovaccine induced effective mild heat in vitro and in vivo to promote antigen presentation. After administrating to MC38 tumor-bearing mice, the hybrid nanovaccine effectively promoted the maturation of DCs, the expansion of cytotoxic T lymphocytes and helper T cells, and the secretion of immunostimulatory cytokines, thereby significantly inhibiting tumor growth.
Topics: Animals; Mice; Hot Temperature; Melanins; Immunotherapy; Immunization; Cancer Vaccines; Dendritic Cells; Neoplasms
PubMed: 37752555
DOI: 10.1186/s12951-023-02106-8 -
Biomolecules Sep 2023The aim of the study was to compare the distribution of corneal and conjunctival epithelial dendritic cells (DCs) in vernal keratoconjunctivitis (VKC), allergic...
The aim of the study was to compare the distribution of corneal and conjunctival epithelial dendritic cells (DCs) in vernal keratoconjunctivitis (VKC), allergic conjunctivitis (AC), and non-allergic controls to examine if the allergy type causes differences in immune cell activation. The prospective study included 60 participants: 20 with VKC, 20 with AC, and 20 non-allergic controls. In vivo confocal microscopy was performed on the right eye. The locations scanned included the corneal centre, inferior whorl, corneal periphery, corneal limbus, and bulbar conjunctiva. The DCs were counted manually, and their morphology was assessed for the largest cell body size, the presence of dendrites, and the presence of long and thick dendrites. The DC density was higher in VKC and AC compared to non-allergic group at all locations ( ≤ 0.01) except at the inferior whorl. The DC density in VKC participants was significantly higher than in AC at the limbus ( < 0.001) but not at other locations. Both the AC and the VKC group had larger DC bodies at the corneal periphery and limbus compared to the non-allergic group ( ≤ 0.03). The study found a higher proportion of participants with DCs exhibiting long dendrites at both the corneal periphery in AC ( = 0.01) and at the corneal centre, periphery, and limbus in VKC, compared to the non-allergic group ( ≤ 0.001). In conclusion, a higher DC density at the limbus may be a marker of more severe VKC. DCs with larger cell bodies and a greater proportion of participants with DCs displaying long dendrites can be potential markers to differentiate allergy from non-allergy, and more severe forms of allergy from milder forms.
Topics: Humans; Conjunctivitis, Allergic; Prospective Studies; Conjunctiva; Cornea; Dendritic Cells
PubMed: 37892151
DOI: 10.3390/biom13101469 -
Frontiers in Immunology 2023Sepsis is a life-threatening condition with high mortality. A few studies have emerged utilizing single-cell RNA sequencing (scRNA-seq) to analyze gene expression at the...
BACKGROUND
Sepsis is a life-threatening condition with high mortality. A few studies have emerged utilizing single-cell RNA sequencing (scRNA-seq) to analyze gene expression at the single-cell resolution in sepsis, but a comprehensive high-resolution analysis of blood antigen-presenting cells has not been conducted.
METHODS
All published human scRNA-seq data were downloaded from the single cell portal database. After manually curating the dataset, we extracted all antigen-presenting cells, including dendritic cells (DCs) and monocytes, for identification of cell subpopulations and their gene profiling and intercellular interactions between septic patients and healthy controls. Finally, we further validated the findings by performing deconvolution analysis on bulk RNA sequencing (RNA-seq) data and flow cytometry.
RESULTS
Within the traditional DC populations, we discovered novel anergic DC subtypes characterized by low major histocompatibility complex class II expression. Notably, these anergic DC subtypes showed a significant increase in septic patients. Additionally, we found that a previously reported immunosuppressive monocyte subtype, Mono1, exhibited a similar gene expression profile to these anergic DCs. The consistency of our findings was confirmed through validation using bulk RNA-seq and flow cytometry, ensuring accurate identification of cell subtypes and gene expression patterns.
CONCLUSIONS
This study represents the first comprehensive single-cell analysis of antigen-presenting cells in human sepsis, revealing novel disease-associated anergic DC subtypes. These findings provide new insights into the cellular mechanisms of immune dysregulation in bacterial sepsis.
Topics: Humans; Dendritic Cells; Clonal Anergy; Monocytes; Sepsis; Single-Cell Analysis
PubMed: 37781404
DOI: 10.3389/fimmu.2023.1257572 -
Cell Reports Oct 2023Advances in the development of therapeutic extracellular vesicles (EVs) for cancer immunotherapy have allowed them to emerge as an alternative to cell therapy. In this...
Advances in the development of therapeutic extracellular vesicles (EVs) for cancer immunotherapy have allowed them to emerge as an alternative to cell therapy. In this proof-of-concept work, we develop bispecific EVs (BsEVs) by genetically engineering EV-producing dendritic cells (DCs) with aCD19 scFv and PD1 for targeting tumor antigens and blocking immune checkpoint proteins simultaneously. We find that these bispecific EVs (EVs-PD1-aCD19) have an impressive ability to accumulate in huCD19-expressing solid tumors following intravenous injection. In addition, EVs-PD1-aCD19 can remarkably reverse the immune landscape of the solid tumor by blocking PD-L1. Furthermore, EVs-PD1-aCD19 can also target tumor-derived EVs in circulation, which prevents the formation of a premetastatic niche in other tissues. Our technology is a demonstration of bispecific EV-based cancer immunotherapy, which may inspire treatments against various types of tumors with different surface antigens and even a patient-tailored therapy.
Topics: Humans; Extracellular Vesicles; Neoplasms; Antigens, Neoplasm; Immunotherapy; Dendritic Cells
PubMed: 37738123
DOI: 10.1016/j.celrep.2023.113138 -
European Journal of Immunology Nov 2023This 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...
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. DC are sentinels of the immune system present in almost every mammalian organ. Since they represent a rare cell population, DC need to be extracted from organs with protocols that are specifically developed for each tissue. This article provides detailed protocols for the preparation of single-cell suspensions from various mouse nonlymphoid tissues, including skin, intestine, lung, kidney, mammary glands, oral mucosa and transplantable tumors. Furthermore, our guidelines include comprehensive protocols for multiplex flow cytometry analysis of DC subsets and feature top tricks for their proper discrimination from other myeloid cells. With this collection, we provide guidelines for in-depth analysis of DC subsets that will advance our understanding of their respective roles in healthy and diseased tissues. 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 coauthors, making it an essential resource for basic and clinical DC immunologists.
Topics: Animals; Humans; Flow Cytometry; Dendritic Cells; Skin; Myeloid Cells; Kidney; Mammals
PubMed: 36512638
DOI: 10.1002/eji.202249819 -
Nano Letters Oct 2023Immunotherapy has emerged as a triumph in the treatment of malignant cancers. Nevertheless, current immunotherapeutics are insufficient in addressing tumors...
Immunotherapy has emerged as a triumph in the treatment of malignant cancers. Nevertheless, current immunotherapeutics are insufficient in addressing tumors characterized by tumor cells' inadequate antigenicity and the tumor microenvironment's low immunogenicity (TME). Herein, we developed a novel multifunctional nanoassembly termed FMMC through the self-assembly of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor 1-methyl-tryptophan prodrug (FM), Ce6, and ionic manganese (Mn) via noncovalent interactions. The laser-ignited FMMC treatment could induce effective immunogenic cell death and activate the STING/MHC-I signaling pathway, thus deeply sculpting the tumor-intrinsic antigenicity to achieve dendritic cell (DC)-dependent and -independent T cell responses against tumors. Meanwhile, by inhibiting IDO-1, FMMC could lead to immunosuppressive TME reversion to an immunoactivated one. FMMC-based phototherapy led to the up-regulation of programmed death-ligand 1 (PD-L1), enhancing the sensitivity of tumors to anti-PD-1 therapy. Furthermore, the incorporation of Mn into FMMC resulted in an augmented longitudinal relaxivity and enhanced the MRI for monitoring the growth of primary tumors and lung metastases. Collectively, the superior reprogramming performance of immunosuppressive tumor cells and TME, combined with excellent anticancer efficacy and MRI capability, made FMMC a promising immune nanosculptor for cancer theranostics.
Topics: Immunotherapy; Phototherapy; T-Lymphocytes; Signal Transduction; Dendritic Cells; Tumor Microenvironment; Cell Line, Tumor
PubMed: 37767907
DOI: 10.1021/acs.nanolett.3c03098