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Cancer vaccine development is inhibited by a lack of strategies for directing dendritic cell (DC) induction of effective tumor-specific cellular immunity. Pathogen engagement of DC lectins and toll-like receptors (TLRs) is thought to shape immunity by directing T cell function. Controlling downstream responses, however, remains a major challenge. A critical goal in advancing vaccine development involves the identification of receptors that drive type 1 cellular immunity. The immune system monitors cells for aberrant glycosylation (a sign of a foreign entity), but potent activation occurs when a second signal, such as single-stranded RNA or lipopolysaccharide, is present to activate TLR signaling. To exploit dual signaling, we engineered a glycan-costumed virus-like particle (VLP) vaccine that displays a DC-SIGN-selective aryl mannose ligand and encapsulates TLR7 agonists. These VLPs deliver programmable peptide antigens to induce robust DC activation and type 1 cellular immunity. In contrast, VLPs lacking this critical DC-SIGN ligand promoted DC-mediated humoral immunity, offering limited tumor control. Vaccination with glycan-costumed VLPs generated tumor antigen-specific Th1 CD4+ and CD8+ T cells that infiltrated solid tumors, significantly inhibiting tumor growth in a murine melanoma model. The tailored VLPs also afforded protection against the reintroduction of tumor cells. Thus, DC lectin-driven immune reprogramming, combined with the modular programmability of VLP platforms, provides a promising framework for directing cellular immunity to advance cancer immunotherapies and vaccines.
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We have exploited the unique physics available in microfluidic devices to engineer a platform capable of integrating all critical elements of cell therapy into a microfluidic device. The platform can be used to isolate, count, identify and culture cells on a device in a closed Current Good Manufacturing Practice-compatible system. We have used the culture and isolation of human mature dendritic cells (DCs) as our model system, demonstrating each critical element in manufacturing a therapeutic product. We used the system to immunomagnetically isolate CD14+ cells from peripheral blood mononuclear cells, perform on-chip enumeration and surface marker characterization to confirm purity of isolation (mean, 98.6 ± 1.6%) and culture cells in the presence of cytokines to drive differentiation to CD83+ mature DCs. Successful DC maturation was confirmed using on-chip surface marker characterization (positive CD83 expression) with process yields comparable to conventional DC production. The technology presented is the first demonstration of a chip bioreactor capable of recapitulation of all critical elements of cell therapy manufacturing. Its closed nature, scalability and integration of both manufacturing and release testing show the potential for a new approach to industrialization and rapid distribution of cell therapies.
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Dendritic cells (DCs) play a crucial role in bridging innate and adaptive immune responses. They are widely distributed in various tissues and organs, including the eyes. In the ocular context, permanent DCs are present at the peripheral edge of the retina and the peripapillary area in an immature state. However, during the inflammatory process, DCs become activated and contribute to the development of uveitis. This review focuses on introducing the characteristics and status of DC-induced uveitis, exploring factors that can influence the status of DCs, and discussing feasible methods for treating DCs in both experimental autoimmune uveitis animal models and humans. It emphasizes the importance of further research on molecular pathways and signaling pathways that regulate the function of DCs. For example, investigating molecules such as cytotoxic T-lymphocyte-associated protein 4, which inhibits the B7-CD28 co-stimulatory interaction, can help improve immune homeostasis. The aim is to identify new therapeutic targets and develop targeted strategies for DCs, such as DC vaccine therapy or the use of immune modulators. These approaches can be tailored to the immune characteristics and disease manifestations of individual patients, enabling personalized treatment strategies. This may include the personalized design and precise medication of DC therapy, with the ultimate goal of improving treatment efficacy while minimizing adverse reactions.
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Psoriatic arthritis (PsA) is an immune-mediated, chronic inflammatory joint disease that commonly occurs as a complication of psoriasis. EGF-like repeats and discoidal I-like domain 3 (EDIL3) is a secreted protein with multiple structural domains and associated with various physiological functions. In this study, we employed a mannan-induced psoriatic arthritis model to investigate the impact of EDIL3 on PsA pathogenesis. Notably, a downregulation of EDIL3 expression was observed in the PsA model, which correlated with increased disease severity. EDIL3 knockout mice exhibited a more severe phenotype of PsA, which was ameliorated upon re-infusion of recombinant EDIL3 protein. The mitigation effect of EDIL3 on PsA depends on its regulation of the activation of monocyte-derived DCs (MoDCs) and T-help 17 cells (Th17). After inhibiting the function of MoDCs and Th17 cells with neutralizing antibodies, the beneficial effects of EDIL3 on PsA were lost. By inducing adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation and suppressing protein kinase B (AKT) phosphorylation, EDIL3 attenuates intracellular glycolysis in MoDCs stimulated by glucose, thereby impeding their maturation and differentiation. Moreover, it diminishes the differentiation of Th17 cells and decelerates the progression of PsA. In conclusion, our findings elucidate the role and mechanism of EDIL3 in the development of PsA, providing a new target for clinical diagnosis and treatment.
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Epithelial injury calls for a regenerative response from a coordinated network of epithelial stem cells and immune cells. Defining this network is key to preserving the repair process for acute resolution, but also for preventing a remodeling process with chronic dysfunction. We recently identified an immune niche for basal-epithelial stem cells using mouse models of injury after respiratory viral infection. Niche function depended on an early sentinel population of monocyte-derived dendritic cells (moDCs) that provided ligand GPNMB to basal-ESC receptor CD44 for reprogramming towards chronic lung disease. These same cell and molecular control points worked directly in mouse and human basal-ESC organoids, but the findings were not yet validated in vivo in human disease. Further, persistence of GPNMB expression in moDCs and M2-macrophages in mouse models suggested utility as a long-term disease biomarker in humans. Here we show increased expression of GPNMB localized to moDC-macrophage populations in lung tissue samples from long-term Covid, asthma, and COPD. The findings thereby provide initial evidence of a persistent and correctable pathway from acute injury to chronic disease with implications for cellular reprogramming and inflammatory memory.
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Anti-aging immunity induced by vaccines was recently reported to enable the elimination of senescent cells. However, the initial immune response to vaccination declines with age, and there is evidence that elderly dendritic cells (DCs) have a reduced capacity to stimulate T cells. Identification of alternative anti-aging vaccine is therefore warranted. Here, we developed a DC vaccine that delivers a cationic protein (CP) fused with the seno-antigen peptides Gpnmb (Gpnmb-CP) into DCs. The Gpnmb-CP-pulsed DC vaccine (Gpnmb-CP-DC) efficiently presented antigens and activated CD8+ T cells, leading to enhanced immune cytotoxicity and memory responses in CD8+ T cells. Thus, the targeted anti-aging immunity triggered by Gpnmb-CP-DC has the ability to selectively eliminate senescent adipocytes and effectively improve age-related metabolic abnormalities in both high-fat diet (HFD)-induced young and aged mice models, as well as in natural aging mouse model. In contrast, the Gpnmb-CP protein vaccine exhibits minimal efficacy in aged mice model. Furthermore, we observed a decreased phagocytic capacity for antigens in aging DCs, accompanied by an upregulation of the immune checkpoint PDL1 expression and a noticeable decline in activated CD8+ T cell. Hence, Gpnmb-CP-DC emerges as a promising vaccine candidate, demonstrating the capacity to induce potent anti-aging immunity, mitigating adipose tissue senescence and metabolic abnormalities, while resilient to the senescent environment of the organism.
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BACKGROUND: Allergic asthma is a chronic bronchial inflammatory disease closely associated with abnormal immune responses of dendritic cells (DCs) and allergen-specific type 2 T helper (Th2) cells. Indirubin (IR), a natural aryl hydrocarbon receptor (AhR) ligand, exerts anti-inflammatory and immunomodulatory properties. PURPOSE: In this study, we aimed to clarify whether IR exhibits immunomodulatory action on DCs via AhR activation and investigated the antiallergic effects of IR in a mouse model of allergic asthma. METHODS: Lipopolysaccharide (LPS)-activated bone marrow-derived DCs were treated with IR. Their mRNA expressions, cytokine production, and phenotype patterns were determined by a quantitative real-time PCR, ELISA, flow cytometry, and RNA sequencing. The mixed lymphocyte reaction was utilized to evaluate the regulatory function of IR-treated DCs on T-cell differentiation. Moreover, mice with ovalbumin (OVA)-induced allergic asthma were treated with IR. Thereafter, the airway hyperresponsiveness (AHR), allergen-specific IgE production, cytokine levels, airway inflammation, and T-cell responses were evaluated. RESULTS: Treatment of LPS-stimulated DCs with 20 µM IR significantly reduced IL-12 and TNF-α production while increasing IL-10 secretion. Meanwhile, these DCs expressed decreased levels of CD80 but increased levels of Jagged 1 surface molecules. However, the effects of IR on DCs were reversed by pretreatment with the AhR antagonist, CH223191. Additionally, the coculture of these tolerogenic-like DCs with allogeneic CD4+T cells promoted the generation of Foxp3+ regulatory T (Treg) cells. A transcriptomic analysis identified several downregulated genes that are involved in regulating cell migration, cytokine secretion, and inflammatory responses in DCs after IR treatment. In an asthmatic murine model, oral administration of 25 mg kg-1 body weight of IR efficiently alleviated the development of AHR, OVA-specific IgE production, and levels of Th2-type cytokines (IL-4, IL-5, and IL-13) and the CCL11 chemokine. IR treatment also attenuated inflammatory cell recruitment and mucus production in the lungs. Notably, an enhanced frequency of Foxp3+ Treg cells and reduced effector T-cell proliferation associated with increased levels of IL-10 and TGF-ß were observed in IR-treated mice. CONCLUSION: IR can induce tolerogenic-like BMDCs which promote the differentiation of Treg cells. Importantly, the expansion of Foxp3+ Treg cells contributed to the therapeutic efficacy of IR against allergic asthma.
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ETHNOPHARMACOLOGICAL RELEVANCE: Periostracum Cicadae (PC), the molted exoskeleton of the cicada Cryptotympana pustulata Fabricius, is frequently employed in Chinese herbal medicine. Based on traditional therapies and pharmacological studies, PC appears to have immunomodulatory activity. However, the specific impact of PC on immunomodulation, particularly its effect on dendritic cells (DCs), remains unknown. DCs act professionally as antigen-presenting cells that trigger adaptive immune responses, making them critical for immunomodulation. MATERIALS AND METHODS: The DCs derived from mouse bone marrow were used to examine the suppressive effect of PC extract on DC activation and maturation. The in vivo suppressive effect was evaluated using a mouse model of contact hypersensitivity (CHS) responses. The determination of the substances in the sample was performed by Liquid chromatography-mass spectrometry/mass spectrometry. RESULTS: The ethyl acetate extract of PC (PCEA) significantly decreased the expressions of proinflammatory cytokines (IL-12, interleukin [IL]-6, as well as tumor necrosis factor [TNF]-α) and surface markers CD80 and CD86 in lipopolysaccharide-stimulated DCs. In the 2,4-dinitro-1-fluorobenzene-induced CHS mouse model, PCEA treatment dramatically attenuated the severity of symptoms. This was evidenced by the alleviation of ear swelling and a reduction in the count of infiltrating CD3+ T cells in the tested ears. In addition, N-acetyldopamine dimer and trimer were identified as major components. CONCLUSION: This study is the first to show that components derived from PCEA inhibit the activation and maturation of DCs as well as CHS responses, indicating they have the potential for treating delayed-type hypersensitivity or DC-related immune disorders.
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Interferon regulatory factor-8 (IRF8) is the lineage determining transcription factor for the type one classical dendritic cell (cDC1) subset, a terminal selector for plasmacytoid dendritic cells and important for the function of monocytes. Studies of Irf8 gene regulation have identified several enhancers controlling its activity during development of progenitors in the bone marrow that precisely regulate expression at distinct developmental stages. Each enhancer responds to distinct transcription factors that are expressed at each stage. IRF8 is first expressed in early progenitors that form the monocyte dendritic cell progenitor (MDP) in response to induction of the transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) acting at the Irf8 +56 kb enhancer. IRF8 levels increase further as the MDP transits into the common dendritic cell progenitor (CDP) in response to E protein activity at the Irf8 +41 kb enhancer. Upon Nfil3-induction in CDPs leading to specification of the cDC1 progenitor, abrupt induction of BATF3 forms the JUN/BATF3/IRF8 heterotrimer that activates the Irf8 +32 kb enhancer that sustains Irf8 autoactivation throughout the cDC1 lifetime. Deletions of each of these enhancers has revealed their stage dependent activation. Surprisingly, studies of compound heterozygotes for each combination of enhancer deletions revealed that activation of each subsequent enhancer requires the successful activation of the previous enhancer in strictly cis-dependent mechanism. Successful progression of enhancer activation is finely tuned to alter the functional accessibility of subsequent enhancers to factors active in the next stage of development. The molecular basis for these phenomenon is still obscure but could have implications for genomic regulation in a broader developmental context.
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Células Dendríticas , Elementos de Facilitación Genéticos , Factores Reguladores del Interferón , Humanos , Factores Reguladores del Interferón/metabolismo , Factores Reguladores del Interferón/genética , Animales , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Elementos de Facilitación Genéticos/genética , Diferenciación Celular , Regulación de la Expresión Génica , Súper PotenciadoresRESUMEN
Dendritic cells (DCs) play a crucial role in orchestrating immune responses, particularly in promoting IFNγ-producing-CD8 cytotoxic T lymphocytes (CTLs) and IFNγ-producing-CD4 T helper 1 (Th1) cells, which are essential for defending against viral infections. Additionally, the nuclear envelope protein lamin A/C has been implicated in T cell immunity. Nevertheless, the intricate interplay between innate and adaptive immunity in response to viral infections, particularly the role of lamin A/C in DC functions within this context, remains poorly understood. In this study, we demonstrate that mice lacking lamin A/C in myeloid LysM promoter-expressing cells exhibit a reduced capacity to induce Th1 and CD8 CTL responses, leading to impaired clearance of acute primary Vaccinia virus (VACV) infection. Remarkably, in vitro-generated granulocyte macrophage colony-stimulating factor bone marrow-derived DCs (GM-CSF BMDCs) show high levels of lamin A/C. Lamin A/C absence on GM-CSF BMDCs does not affect the expression of costimulatory molecules on the cell membrane but it reduces the cellular ability to form immunological synapses with naïve CD4 T cells. Lamin A/C deletion induces alterations in NFκB nuclear localization, thereby influencing NF-κB-dependent transcription. Furthermore, lamin A/C ablation modifies the gene accessibility of BMDCs, predisposing these cells to mount a less effective antiviral response upon TLR stimulation. This study highlights the critical role of DCs in interacting with CD4 T cells during antiviral responses and proposes some mechanisms through which lamin A/C may modulate DC function via gene accessibility and transcriptional regulation.
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Células Dendríticas , Lamina Tipo A , Ratones Endogámicos C57BL , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Animales , Lamina Tipo A/metabolismo , Lamina Tipo A/genética , Ratones , FN-kappa B/metabolismo , Virus Vaccinia/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Ratones Noqueados , Vaccinia/inmunología , Células TH1/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Sinapsis Inmunológicas/metabolismo , Sinapsis Inmunológicas/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismoRESUMEN
Tuberculosis (TB) is one of the leading causes of death from infectious diseases, killing approximately 1.3 million people worldwide in 2022 alone. The current vaccine for TB contains a live attenuated bacterium, Mycobacterium bovis BCG (Bacille Calmette-Guérin). The BCG vaccine is highly effective in preventing severe forms of childhood TB but does not protect against latent infection or disease in older age groups. A new or improved BCG vaccine for prevention of pulmonary TB is urgently needed. In this study, we infected murine bone marrow derived dendritic cells from C57BL/6 mice with M. bovis BCG followed by elution and identification of BCG-derived MHC class I and class II-bound peptides using tandem mass spectrometry. We identified 1436 MHC-bound peptides of which 94 were derived from BCG. Fifty-five peptides were derived from MHC class I molecules and 39 from class II molecules. We tested the 94 peptides for their immunogenicity using IFN- γ ELISPOT assay with splenocytes purified from BCG immunized mice and 10 showed positive responses. Seven peptides were derived from MHC II and three from MHC class I. In particular, MHC class II binding peptides derived from the mycobacterial surface lipoprotein Mpt83 were highly antigenic. Further evaluations of these immunogenic BCG peptides may identify proteins useful as new TB vaccine candidates.
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Antígenos Bacterianos , Vacuna BCG , Proteínas Bacterianas , Células Dendríticas , Ratones Endogámicos C57BL , Mycobacterium bovis , Animales , Antígenos Bacterianos/inmunología , Mycobacterium bovis/inmunología , Ratones , Vacuna BCG/inmunología , Proteínas Bacterianas/inmunología , Células Dendríticas/inmunología , Desarrollo de Vacunas , Femenino , Proteómica/métodos , Linfocitos T/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Lipoproteínas/inmunología , Tuberculosis/prevención & control , Tuberculosis/inmunología , Péptidos/inmunología , Proteínas de la MembranaRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic malignancy with limited treatment options. Currently, standard treatment strategies include clinical trials; chemotherapy regimens such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD); and tagraxofusp-erzs (TAG, previously SL-401) which is the first-in-class targeted therapy against CD123. TAG received Food and Drug Administration approval for frontline BPDCN treatment in December 2018 and has increasingly become an alternative to chemotherapy, offering potentially more effective and less toxic options. However, despite promising results, there are still patients who may be resistant to TAG monotherapy and/or who respond but eventually relapse. Herein, we discuss an important patient case of BPDCN treated with TAG and review BPDCN treatment strategies.
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BACKGROUND: High-grade gliomas (HGG) are the most aggressive primary brain tumors with poor prognoses despite conventional treatments. Immunotherapy has emerged as a promising avenue due to its potential to elicit a targeted immune response against tumor cells. OBJECTIVE: This meta-analysis aimed to evaluate the efficacy and safety of various immunotherapeutic strategies, including immune checkpoint inhibitors (ICI), virotherapy, and dendritic cell vaccines (DCV) in treating HGG. METHODS: Following the PRISMA framework, we searched PubMed, Cochrane, and Embase for studies reporting outcomes of HGG patients treated with immunotherapy. Key metrics included overall survival, progression-free survival, and treatment-related adverse events. RESULTS: We reviewed 47 studies, analyzing data from 3674 HGG patients treated with immunotherapy. The mean overall survival for patients treated with ICI was 11.05 months, with virotherapy at 11.79 months and notably longer for DCV at 24.11 months. The mean progression-free survival (PFS) for ICIs was 3.65 months. Virotherapy demonstrated a PFS favoring the control group, indicating minimal impact, while DCV showed substantial PFS improvement with a median of 0.43 times lower hazard compared to controls (95% CI: 29-64%). Adverse events were primarily Grade 1 or 2 for ICI, included a Grade 5 event for virotherapy, and were predominantly Grade 1 or 2 for DCV, indicating a favorable safety profile. CONCLUSION: Immunotherapy holds potential as an effective treatment for HGG, especially DCV. However, results vary significantly with the type of therapy and individual patient profiles. Further randomized controlled trials are necessary to establish robust clinical guidelines and optimize treatment protocols.
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BACKGROUND: Dendritic cell (DC) vaccines show promise for glioma treatment, but optimal use remains uncertain. This meta-analysis examined DC vaccine efficacy and safety for gliomas. METHODS: This systematic review and meta-analysis study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. From the date of inception to October 23, 2023, electronic databases PubMed, Embase, Web of Science, and Scopus have been thoroughly evaluated. RESULTS: A total of 12 studies with 998 patients and a mean age ranging from 40.2 to 56 years were included. Across 12 articles, DC vaccine 6-month overall survival (OS) was 100% [95% confidence interval {95%CI}: 100%-100%]. Respectively, 12-month OS reported 75% [95%CI: 65%-85%] but declined to 32% [95%CI: 20%-43%] for 24-month OS. 6- and 12-month progression-free survival reached 49% [95%CI: 21%-77%] and 19% [95%CI:8%-30%]. Studying radiological outcomes shows that complete response and partial response rates were 13% [95%CI: 17%-42%], and 26% [95%CI: 10%-42%], though stable disease reached 33% [95%CI: 15%-51%], suggesting predominant antineoplastic effects. The progressive disease rate also was 24% [95%CI: 9%-57%]. CONCLUSIONS: In gliomas, DC vaccinations show a temporary efficacy; stability is more prevalent than regression. Impacts favor decreased resistance to early disease. Enhancing efficacy remains critical. Early therapy can be enhanced by appropriate supplementary therapy integration.
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There are no effective treatment options for patients with poor performance status and limited liver reserve, classified as Child-Pugh Grade B and C. A 61-year-old man with a prior medical history of hepatitis C virus infection was admitted to the hospital with abdominal distension and significant abdominal ascites. He was diagnosed with stage IVB hepatocellular carcinoma (HCC), characterized by multiple metastases to lymph nodes, lungs, and bones. After receiving combined immune therapy, including dendritic cell therapy targeting WT1 and α-Galactosylceramide, natural killer cells, and Nivolumab, the patient showed significant improvement in HCC and liver reserve function and followed standard treatment. Combined immune therapy is potentially an important option for patients with advanced hepatocellular carcinoma and poor liver reserve function, especially for relatively young patients.
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Introduction: Immunotherapy represents a promising breakthrough in cancer management and is being explored in canine melanomas. Dendritic cells (DCs) play a crucial role in priming T-cell-mediated immune reactions through the antigen-presenting function. Combining immunotherapy and radiation therapy may generate more substantial anti-cancer efficacy through immunomodulation. Objectives: Our research reported a preliminary result of the safety and outcome of a kind of immunotherapy, the allogeneic dendritic cell and autologous tumor cell fusion vaccine, alone or in combination with hypofractionated radiation therapy, in canine oral malignant melanoma. Methods: Two groups of dogs with histopathological diagnoses of oral malignant melanoma were recruited. In group 1 (DCRT), dogs received a combination of DC fusion vaccine and radiotherapy. In group 2 (DC), dogs received DC fusion vaccine alone. DC vaccination was given once every 2 weeks for four doses. Radiotherapy was performed weekly for five fractions. Dogs that received carboplatin were retrospectively collected as a control group (group 3). Results: Five dogs were included in group 1 (two stage II, three stage III), 11 in group 2 (three stage I/II, eight stage III/IV), and eight (two stage I/II, six stage III/IV) in the control group. Both DC and DCRT were well-tolerated, with only mild adverse events reported, including mucositis, gastrointestinal discomfort, and injection site reactions. The median progression-free intervals in groups 1, 2, and 3 were 214 (95% CI, NA, due to insufficient data), 100 (95% CI, 27-237), and 42 days (95% CI, NA-170), respectively, which were not significantly different. The 1-year survival rates were 20, 54.5, and 12.5% in groups 1, 2, and 3. Dogs in the DCRT group exhibited significantly higher TGF-ß signals than the DC group throughout the treatment course, indicating a possible higher degree of immunosuppression. Conclusion: The manuscript demonstrated the safety of dendritic cell/tumor cell fusion vaccine immunotherapy, alone or in combination with radiotherapy. The results support further expansion of this immunotherapy, modification of combination treatment and protocols, and investigation of combining DC vaccine with other treatment modalities. Clinical trial registration: Preclinical Trials, PCTE0000475.
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Detection of cytosolic DNA by the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING) pathway provides immune defense against pathogens and cancer but can also cause autoimmunity when overactivated. The exonuclease three prime repair exonuclease 1 (TREX1) degrades DNA in the cytosol and prevents cGAS activation by self-DNA. Loss-of-function mutations of the TREX1 gene are linked to autoimmune diseases such as Aicardi-Goutières syndrome, and mice deficient in TREX1 develop lethal inflammation in a cGAS-dependent manner. In order to determine the type of cells in which cGAS activation drives autoinflammation, we generated conditional cGAS knockout mice on the Trex1-/- background. Here, we show that genetic ablation of the cGAS gene in classical dendritic cells (cDCs), but not in macrophages, was sufficient to rescue Trex1-/- mice from all observed disease phenotypes including lethality, T cell activation, tissue inflammation, and production of antinuclear antibodies and interferon-stimulated genes. These results show that cGAS activation in cDC causes autoinflammation in response to self-DNA accumulated in the absence of TREX1.
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Autoinmunidad , Células Dendríticas , Exodesoxirribonucleasas , Ratones Noqueados , Nucleotidiltransferasas , Fosfoproteínas , Animales , Exodesoxirribonucleasas/genética , Exodesoxirribonucleasas/deficiencia , Exodesoxirribonucleasas/metabolismo , Nucleotidiltransferasas/genética , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/deficiencia , Células Dendríticas/inmunología , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosfoproteínas/inmunología , Ratones , Autoinmunidad/inmunología , Malformaciones del Sistema Nervioso/genética , Malformaciones del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/patología , Inflamación/inmunología , Inflamación/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/genéticaRESUMEN
Hepatocellular carcinoma (HCC) exhibits a low response to immunotherapy due to the dense extracellular matrix (ECM) filled with immunosuppressive cells including dendritic cells (DCs) of blocked maturation. Herein, we develop a nanoprodrug self-assembled from polyethylene glycol-poly-4-borono-l-phenylalanine (mPEG-PBPA) conjugating with quercetin (QUE) via boronic ester bonds. In addition, an immune adjuvant of imiquimod (R837) is incorporated. The nanodrug (denoted as Q&R@NPs) is prepared from a simple mixing means with a high loading content of QUE reaching more than 30%. Owing to the acid and reactive oxygen species (ROS) sensitivities of boronic ester bonds, Q&R@NPs can respond to the tumor microenvironment (TME) and release QUE and R837 to synchronously exert multicellular regulation functions. Specifically, QUE inhibits the activation state of hepatic stellate cells and reduces highly expressed programmed death receptor ligand 1 (PD-L1) on tumor cells, meanwhile R837 exposes calreticulin on tumor cell surface as an "eat me" signal and leads to a large number of DCs maturing for enhanced antigen presentation. Consequently, the cooperative immune regulation results in a remodeled TME with high infiltration of cytotoxic T lymphocytes for enhanced HCC immunotherapy, which demonstrates an effective immunotherapy paradigm for dense ECM characterized solid tumors with high PD-L1 expression.
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BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic malignancy originating from the precursors of plasmacytoid dendritic cells. BPDCN often involves the skin, lymph nodes, and bone marrow, with rapid clinical progression and a poor prognosis. The BPDCN diagnosis is mainly based on the immunophenotype. CASE SUMMARY: In this paper, we retrospectively analyzed 2 cases of BPDCN. Both patients were elderly males. The lesions manifested as skin masses. Morphological manifestations included diffuse and dense tumor cell infiltration of the dermis and subcutaneous tissues. Immunohistochemistry staining showed that cluster of differentiation CD4, CD56, CD43, and CD123 were positive. CONCLUSION: In this paper, we retrospectively analyzed 2 cases of BPDCN. Both patients were elderly males. The lesions manifested as skin masses. Morphological manifestations included diffuse and dense tumor cell infiltration of the dermis and subcutaneous tissues. Immunohistochemistry staining showed that cluster of differentiation CD4, CD56, CD43, and CD123 were positive.
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TDC are hematopoietic cells with unique features that provide intriguing insights into the interplay between innate and adaptive immunity. They express a combination of conventional dendritic cell (DC) and T-cell markers and are found in secondary lymphoid organs (SLOs), lungs and liver of naïve mice, as well as in human blood. When analyzed ex vivo, TDC can behave either as DCs or as T cells, depending on the provided stimuli. Notably, TDC numbers and activation significantly increase in SLOs following viral infection, suggesting a potential role for TDC in antiviral immune responses. In this review, we discuss the properties of these fascinating cells, which call for more investigation on their physiological role during immune responses to both pathogens and tumors.