Ex vivo-generated dendritic cell-based vaccines in melanoma: the role of nanoparticulate delivery systems

Immunotherapy ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 333-349 ◽  
Author(s):  
Mona Yazdani ◽  
Mahmoud Reza Jaafari ◽  
Javad Verdi ◽  
Behrang Alani ◽  
Mahdi Noureddini ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Ex Vivo ◽  
Treatment Strategies ◽  
Delivery Systems ◽  
Antigen Delivery ◽  
Effective Delivery ◽  
Potential Applicability ◽  
Nanoparticulate Delivery ◽  
Dc Maturation

Melanoma is a poor immunogenic cancer and many treatment strategies have been used to enhance specific or nonspecific immunity against it. Dendritic cell (DC)-based cancer vaccine is the most effective therapies that have been used so far. Meanwhile, the efficacy of DC-based immunotherapy relies on critical factors relating to DCs such as the state of maturation and proper delivery of antigens. In this regard, the use of nanoparticulate delivery systems for effective delivery of antigen to ex vivo-generated DC-based vaccines that also poses adjuvanticity would be an ideal approach. In this review article, we attempt to summarize the role of different types of nanoparticulate antigen delivery systems used in the development of ex vivo-generated DC-based vaccines against melanoma and describe their adjuvanticity in mediation of DC maturation, cytoplasmic presentation of antigens to MHC class I molecules, which led to potent antigen-specific immune responses. As were represented, cationic liposomes were the most used approach, which suggest its potential applicability as delivery systems for further experiments in combination with either adjuvants or monoclonal antibodies.

scholarly journals Implantable vaccines: a solution for immune system manipulation to any antigenic stimulus

2020 ◽  
Vol 4 (4) ◽  
pp. 5-11
Author(s):  
Ioanna Zerva ◽  
Vasileia Pateraki ◽  
Irene Athanassakis
Keyword(s):  
Immune Response ◽  
Ex Vivo ◽  
Great Majority ◽  
Delivery Systems ◽  
Antigen Delivery ◽  
Immune Responsiveness ◽  
Antigenic Stimulus ◽  
Human Pathology ◽  
Check Points ◽  
Antigen Delivery Systems

Effective and side-effect-free vaccines are still difficult tasks to achieve for a great majority of antigenic stimuli. Pathogen manipulation to abort infectivity and antigen delivery to ensure immune responsiveness are the major components vaccine technology tries to resolve. However, the development of an immune response is still a complicated matter, lies on hundreds of parameters and any effort towards activation can easily lead to adverse effects, making immunotherapy very difficult to control. The present review attempts to highlight the major parameters affecting immune responsiveness and show that vaccine technology, except from pathogen manipulation and the development of antigen delivery systems, requires attention to additional check-points. Analyzing the recently described personalized implantable vaccine technology, it becomes obvious that the nature of each antigenic stimulus dictates different responsiveness to the organism, which discourages the use of universal adjuvant and antigen-delivery systems. On the contrary, the ex vivo tuning of the immune response proposed by the implantable vaccine technology, allows controllable amendment of the response. The development of personalized technologies is expected to provide valuable tools for the management of human pathology.

Mucosal Dendritic Cell Subsets Control HIV-1’s Viral Fitness

2020 ◽  
Vol 7 (1) ◽  
pp. 385-402
Author(s):  
Bernadien M. Nijmeijer ◽  
Catharina J.M. Langedijk ◽  
Teunis B.H. Geijtenbeek
Keyword(s):  
Dendritic Cell ◽  
Sexual Transmission ◽  
Treatment Strategies ◽  
Viral Fitness ◽  
Immunodeficiency Virus ◽  
Novel Treatment Strategies ◽  
Hiv 1 ◽  
Selection Of

Dendritic cell (DC) subsets are abundantly present in genital and intestinal mucosal tissue and are among the first innate immune cells that encounter human immunodeficiency virus type 1 (HIV-1) after sexual contact. Although DCs have specific characteristics that greatly enhance HIV-1 transmission, it is becoming evident that most DC subsets also have virus restriction mechanisms that exert selective pressure on the viruses during sexual transmission. In this review we discuss the current concepts of the immediate events following viral exposure at genital mucosal sites that lead to selection of specific HIV-1 variants called transmitted founder (TF) viruses. We highlight the importance of the TF HIV-1 phenotype and the role of different DC subsets in establishing infection. Understanding the biology of HIV-1 transmission will contribute to the design of novel treatment strategies preventing HIV-1 dissemination.

Rhodiola and salidroside in the treatment of metabolic disorders

2019 ◽  
Vol 19 (19) ◽  
pp. 1611-1626 ◽  
Author(s):  
Xiang-Li Bai ◽  
Xiu-Ling Deng ◽  
Guang-Jie Wu ◽  
Wen-Jing Li ◽  
Si Jin
Keyword(s):  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Ex Vivo ◽  
Treatment Strategies ◽  
Ampk Signaling ◽  
Beneficial Effects

Over the past three decades, the knowledge gained about the mechanisms that underpin the potential use of Rhodiola in stress- and ageing-associated disorders has increased, and provided a universal framework for studies that focused on the use of Rhodiola in preventing or curing metabolic diseases. Of particular interest is the emerging role of Rhodiola in the maintenance of energy homeostasis. Moreover, over the last two decades, great efforts have been undertaken to unravel the underlying mechanisms of action of Rhodiola in the treatment of metabolic disorders. Extracts of Rhodiola and salidroside, the most abundant active compound in Rhodiola, are suggested to provide a beneficial effect in mental, behavioral, and metabolic disorders. Both in vivo and ex vivo studies, Rhodiola extracts and salidroside ameliorate metabolic disorders when administered acutely or prior to experimental injury. The mechanism involved includes multi-target effects by modulating various synergistic pathways that control oxidative stress, inflammation, mitochondria, autophagy, and cell death, as well as AMPK signaling that is associated with possible beneficial effects on metabolic disorders. However, evidence-based data supporting the effectiveness of Rhodiola or salidroside in treating metabolic disorders is limited. Therefore, a comprehensive review of available trials showing putative treatment strategies of metabolic disorders that include both clinical effective perspectives and fundamental molecular mechanisms is warranted. This review highlights studies that focus on the potential role of Rhodiola extracts and salidroside in type 2 diabetes and atherosclerosis, the two most common metabolic diseases.

scholarly journals AB0129 PCSK9 IS ASSOCIATED WITH DISEASE ACTIVITY AND IMPLICATED IN IMMUNE ACTIVATION IN SYSTEMIC LUPUS ERYTHEMATOSUS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1365.1-1366
Author(s):  
A. Liu ◽  
M. Rahman ◽  
I. Hafström ◽  
S. Ajeganova ◽  
J. Frostegård
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Cardiovascular Disease ◽  
Dendritic Cell ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Ex Vivo ◽  
Human Peripheral Blood ◽  
Oxidized Ldl ◽  
Systemic Lupus ◽  
Dc Maturation

Background:LDL-levels are increased by Proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL-receptor (LDLR). We reported that PCSK9 has immune modulatory properties in addition to LDL-lowering and ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL)1, which is abundant in atherosclerotic plaques. OxLDL is also raised and associated with cardiovascular disease (CVD) in SLE.1-3Objectives:We here investigate the role of PCSK9 in SLE both in a clinical context and in experimental ex vivo studies. The objective is to investigate if PCSK9 and its inhibition could be of relevance in SLE in addition to LDL-level related propertiesMethods:PCSK9-levels were determined by ELISA among SLE patients (n=109) and age- and sex-matched population-based controls (n=91). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded by echogenicity. Human peripheral blood monocytes from SLE patients or controls were differentiated into DCs. Effects of PCSK9 and its inhibition by silencing were studied.Results:PCSK9-levels were non-significantly higher among SLE-patients as compared to controls but associated significantly with SLE disease activity, as determined by SLAM (0.020) or SLEDAI (0.0178). There was no association between PCSK9-levels and atherosclerosis as determined by IMT, prevalence of plaques or echolucent (potentially vulnerable) plaques. PCSK9 levels were significantly associated with CVD among SLE-patients but not after adjustment for age.OxLDL induced PCSK9 in DCs and DC-maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DC from SLE patients than from controls. Silencing of PCSK9 abolished OxLDL-induced DC-maturation.Conclusion:PCSK9 is associated with disease activity in SLE. One underlying cause could be OxLDL, promoting DC-activation which depends on PCSK9. OxLDL induces PCSK9, an effect which is higher among SLE-patients.PCSK9 could play an unexpected immunological role in SLE and inhibition of PCSK9 could potentially play a role in disease amelioration, pending on clinical studies.References:[1]Liu A and Frostegard J. PCSK9 plays a novel immunological role in oxidized LDL-induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque.J Intern Med. 2018.[2]Frostegard J, Svenungsson E, Wu R, Gunnarsson I, Lundberg IE, Klareskog L, Horkko S and Witztum JL. Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestations.Arthritis Rheum. 2005;52:192-200.[3]Frostegard J. Immunity, atherosclerosis and cardiovascular disease.BMC Med. 2013;11:117.Disclosure of Interests:Anquan Liu: None declared, Mizanur Rahman: None declared, Ingiäld Hafström: None declared, Sofia Ajeganova: None declared, Johan Frostegård Grant/research support from: Unconditional competitive grant from Amgen, related only to PCSK9, not the topic of this abstract

scholarly journals Oxytocin signalling in dendritic cells regulates immune tolerance in the intestine and alleviates DSS-induced colitis

2021 ◽  
Vol 135 (4) ◽  
pp. 597-611
Author(s):  
Dandan Dou ◽  
Jinghui Liang ◽  
Xiangyu Zhai ◽  
Guosheng Li ◽  
Hongjuan Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Akt Pathway ◽  
T Helper 1 ◽  
Colon Tissue ◽  
Cytokine Modulation ◽  
Inflammatory Bowel ◽  
Dc Maturation

Abstract Background: Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that is associated with immune dysfunction. Recent studies have indicated that the neurosecretory hormone oxytocin (OXT) has been proven to alleviate experimental colitis. Methods: We investigated the role of OXT/OXT receptor (OXTR) signalling in dendritic cells (DCs) using mice with specific OXTR deletion in CD11c+ cells (OXTRflox/flox×CD11c-cre mice) and a dextran sulfate sodium (DSS)-induced colitis model. Results: The level of OXT was abnormal in the serum or colon tissue of DSS-induced colitis mice or the plasma of UC patients. Both bone marrow-derived DCs (BMDCs) and lamina propria DCs (LPDCs) express OXTR. Knocking out OXTR in DCs exacerbated DSS-induced acute and chronic colitis in mice. In contrast, the injection of OXT-pretreated DCs significantly ameliorated colitis. Mechanistically, OXT prevented DC maturation through the phosphatidylinositol 4,5-bisphosphate 3-kinase (Pi3K)/AKT pathway and promoted phagocytosis, adhesion and cytokine modulation in DCs. Furthermore, OXT pre-treated DCs prevent CD4+ T cells differentiation to T helper 1 (Th1) and Th17. Conclusions: Our results suggest that OXT-induced tolerogenic DCs efficiently protect against experimental colitis via Pi3K/AKT pathway. Our work provides evidence that the nervous system participates in the immune regulation of colitis by modulating DCs. Our findings suggest that generating ex vivo DCs pretreated with OXT opens new therapeutic perspectives for the treatment of UC in humans.

scholarly journals Combining 1,4-dihydroxy quininib with Bevacizumab/FOLFOX alters angiogenic and inflammatory secretions in ex vivo colorectal tumors

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Susan A. Kennedy ◽  
Maria E. Morrissey ◽  
Margaret R. Dunne ◽  
Fiona O’Connell ◽  
Clare T. Butler ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Ex Vivo ◽  
Alternative Pathway ◽  
Combined Treatment ◽  
Poor Responders ◽  
Colorectal Tumors ◽  
Secreted Expression ◽  
Dc Maturation ◽  
Tumor Eradication ◽  
Related Mortality

Abstract Background Colorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC (mCRC). In mCRC cases, the 5-year survival rate remains at approximately 14%, reflecting the lack of effectiveness of currently available treatments such as the anti-VEGF targeting antibody Bevacizumab combined with the chemotherapy folinic acid, fluorouracil and oxaliplatin (FOLFOX). Approximately 60% of patients do not respond to this combined treatment. Furthermore, Bevacizumab inhibits dendritic cell (DC) maturation in poor responders, a key process for tumor eradication. Method Following drug treatment, secreted expression levels of angiogenic and inflammatory markers in tumor conditioned media generated from human ex vivo colorectal tumors were measured by ELISA. Dendritic cell phenotypic and maturation markers were assessed by flow cytometry. Results Our novel compound, 1,4-dihydroxy quininib, acts in an alternative pathway compared to the approved therapy Bevacizumab. 1,4-dihydroxy quininib alone, and in combination with Bevacizumab or FOLFOX significantly reduced TIE-2 expression which is involved in the promotion of tumor vascularization. Combination treatment with 1,4-dihydroxy quininib significantly increased the expression level of DC phenotypic and maturation markers. Conclusion Our results indicate the anti-angiogenic small molecule 1,4-dihydroxy quininib could be an alternative novel treatment in combination therapy for CRC patients.

scholarly journals Dendritic Cell Vaccines for Cancer Immunotherapy: The Role of Human Conventional Type 1 Dendritic Cells

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 158 ◽  
Author(s):  
João Calmeiro ◽  
Mylène A. Carrascal ◽  
Adriana Ramos Tavares ◽  
Daniel Alexandre Ferreira ◽  
Célia Gomes ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Ex Vivo ◽  
Great Effort ◽  
Tumor Vaccines ◽  
Conventional Type

Throughout the last decades, dendritic cell (DC)-based anti-tumor vaccines have proven to be a safe therapeutic approach, although with inconsistent clinical results. The functional limitations of ex vivo monocyte-derived dendritic cells (MoDCs) commonly used in these therapies are one of the pointed explanations for their lack of robustness. Therefore, a great effort has been made to identify DC subsets with superior features for the establishment of effective anti-tumor responses and to apply them in therapeutic approaches. Among characterized human DC subpopulations, conventional type 1 DCs (cDC1) have emerged as a highly desirable tool for empowering anti-tumor immunity. This DC subset excels in its capacity to prime antigen-specific cytotoxic T cells and to activate natural killer (NK) and natural killer T (NKT) cells, which are critical factors for an effective anti-tumor immune response. Here, we sought to revise the immunobiology of cDC1 from their ontogeny to their development, regulation and heterogeneity. We also address the role of this functionally thrilling DC subset in anti-tumor immune responses and the most recent efforts to apply it in cancer immunotherapy.

Selective Tumor-Specific Antigen Delivery to Dendritic Cells Using Mannose-Labeled Poly(d, l-lactide-co-glycolide) Nanoparticles for Cancer Immunotherapy

2020 ◽  
Vol 16 (2) ◽  
pp. 201-211 ◽  
Author(s):  
Tae In Wi ◽  
Yeongseon Byeon ◽  
Ji Eun Won ◽  
Jae Myeong Lee ◽  
Tae Heung Kang ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Targeted Delivery ◽  
Ex Vivo ◽  
Specific Antigen ◽  
Plga Nanoparticles ◽  
Antigen Delivery ◽  
Viral Vaccine ◽  
Effective Delivery ◽  
Specific Antigens ◽  
Mannose Receptors

A key issue in dendritic cell (DC)-based cancer immunotherapy is the effective delivery of tumor-specific antigens to DCs. To deliver antigens, non-viral vaccine system has been used in ex vivo manipulation. However, ex vivo manipulation is time-consuming, lacks quality control of DCs, and demonstrates low antigen delivery efficiency, which implicates that there are serious problems in therapeutic DC preparations. Therefore, we developed mannose (MN)-labeled poly(d, l-lactide-co-glycolide) (PLGA) nanoparticles (MN-PLGA-NPs) encapsulating tumor-specific antigens for targeted delivery to mannose receptors (MN-R) on DC surfaces without ex vivo manipulation. The MN-PLGA-NPs showed DC-selective delivery in tumor-bearing mice, leading to highly mature and activated DCs, which migrated to lymphoid organs, resulting in activation of cytotoxic CD8+ T cells. Additionally, MN-PLGA-NPs showed significant therapeutic efficacy in EG7 lymphoma tumorbearing mice. Our nano-platform technology can be used as a vaccine system to bypass ex vivo manipulation and enhance targeted delivery of tumor-specific antigens to DCs, which is well-suited for cancer immunotherapy.

scholarly journals Cross-Presenting XCR1+ Dendritic Cells as Targets for Cancer Immunotherapy

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 565 ◽  
Author(s):  
Katherine M. Audsley ◽  
Alison M. McDonnell ◽  
Jason Waithman
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Treatment Strategies ◽  
Vital Role ◽  
Cell Responses ◽  
Cell Immunity ◽  
Patient Responses

The use of dendritic cells (DCs) to generate effective anti-tumor T cell immunity has garnered much attention over the last thirty-plus years. Despite this, limited clinical benefit has been demonstrated thus far. There has been a revival of interest in DC-based treatment strategies following the remarkable patient responses observed with novel checkpoint blockade therapies, due to the potential for synergistic treatment. Cross-presenting DCs are recognized for their ability to prime CD8+ T cell responses to directly induce tumor death. Consequently, they are an attractive target for next-generation DC-based strategies. In this review, we define the universal classification system for cross-presenting DCs, and the vital role of this subset in mediating anti-tumor immunity. Furthermore, we will detail methods of targeting these DCs both ex vivo and in vivo to boost their function and drive effective anti-tumor responses.

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