Effector Functions of Dendritic Cells in Cancer: Role of Cytotoxicity and Growth Inhibition.

The tumor microenvironment plays a critical role in modulating immune responses associated with tumorigenesis, tumor progression, and metastasis. Dendritic cells (DC) play a key role in preventing and progression of metastatic neoplasia by driving and restoring dysfunctional immune systems and obliterating immunosuppression, thus obstructing tumor evasion. In this review, we will discuss the functions of tumor-infiltrating DC in anti-tumor resistance, prevention of tumor recurrence, and immunosuppression. We will also describe DC metabolism, differentiation, and plasticity, which are essential for its function. Cancers like Lymphomas may be able to corrupt immune surveillance by reducing natural killer cell numbers. Thus, interactions between lymphoma and DC with reference to cytotoxicity may be an important event, likely to be mediated via activation with interferon-γ (IFN-γ) and Toll like receptors (TLR) ligands. Mechanisms of DC-mediated cytotoxicity and the role of apoptosis and death receptors, including the role played by nitric oxide, etc., are of immense significance. We will also look into the molecular mechanisms in the tumor microenvironment, reduced drug sensitivity, and tumor relapse, as well as methods for combating drug resistance and focusing on immunosuppressive tumor networks. We will address how DC mediated cytotoxicity in combination with drugs affects tumor growth and expansion in relation to checkpoint inhibitors and regulatory T cells. Innovative approaches for therapeutic modulation of this immunosuppressive adoptive DC immunotherapy will be highlighted, which is necessary for future personalized therapeutic applications.

Crucial role of dendritic cells in the generation of anti-tumor T-cell responses and immunogenic tumor microenvironment to suppress tumor development.

Dendritic cells (DCs) are known as unique professional antigen (Ag)-presenting cells (APCs) to prime naïve T cells for the initiation of adaptive immunity. While DCs are believed to play a pivotal role in generating anti-tumor T-cell responses, the importance of DCs in the protection from the progression of tumors remains elusive. Here, we show how the constitutive deficiency of CD11chi DCs influences the progression of tumors with the use of binary transgenic mice with constitutive loss of CD11chi DCs. Constitutive loss of CD11chi DCs not only enhances the progression of tumors but also reduces the responses of Ag-specific T cells. Furthermore, the congenital deficiency of CD11chi DCs generates the immunosuppressive tumor microenvironment (TME) that correlates with the marked accumulation of myeloid-derived suppressor cells (MDSCs) and the prominent productions of immunosuppressive mediators. Thus, our findings suggest that CD11chi DCs are crucial for generating anti-tumor T-cell responses and immunogenic TME to suppress the development of tumors.

Conventional dendritic cells are more activated in the hyperplastic Thymus of myasthenia gravis patients.

INTRODUCTION: Dendritic cells (DCs) are crucial to form ectopic germinal centers (GCs) in the hyperplastic thymus (HT), which are typically found in anti-acetylcholine receptor autoantibody-positive myasthenia gravis (MG) patients. However, the characteristics of such DCs in the HT and their roles in thymic hyperplasia formation remain unclear. METHODS: We collected thymic tissue from MG patients and patients who underwent cardiac surgery. The tissues were cut into sections for immunohistochemistry and immunofluorescence or digested into a single cell suspension for flow cytometry. RESULTS: In addition to formation of ectopic GCs, we found that the proportion of the medulla in the thymic parenchyma was higher than that in the cortex (areacortex/areamedulla, 1.279 vs. 0.6576) in the HT of MG patients. The density of conventional dendritic cells (cDCs) in the HT was 131 ± 64.36 per mm2, whereas in normal thymic tissue, the density was 59.17 ± 22.54 per mm2. The more abundant cDCs expressed co-stimulatory molecules (CD80 and CD86) strongly. Moreover, the more abundant subset was mainly CD141+ DCs (cDC1s), accounting for an increase from 15% to 29%. However, these increased cDC1s appeared to be unrelated to Hassall's corpuscles and ectopic GCs. CONCLUSION: Thymic hyperplasia in MG patients is manifested as an increase in the proportion of the thymic medulla accompanied by increases in the density and functional activation as well as changes in the subset composition of cDCs.

An IL-23-STAT4 pathway is required for the proinflammatory function of classical dendritic cells during CNS inflammation.

Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. To define whether STAT4 is required for intrinsic signaling in mature DC function, we used conditional mutant mice in the EAE model. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the central nervous system. EAE susceptibility was recovered following adoptive transfer of wild-type bone marrow-derived DCs to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single-cell RNA-sequencing (RNA-seq) identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define an IL-23-STAT4 pathway in DCs that is key to DC function during inflammatory disease.

Current mRNA-based vaccine strategies for glioma treatment.

Gliomas are one of the most aggressive types of brain tumors and are associated with high morbidity and mortality rates. Currently, conventional treatments for gliomas such as surgical resection, radiotherapy, and chemotherapy have limited effectiveness, and new approaches are needed to improve patient outcomes. mRNA-based vaccines represent a promising therapeutic strategy for cancer treatment, including gliomas. Recent advances in immunotherapy using mRNA-based dendritic cell vaccines have shown great potential in preclinical and clinical trials. Dendritic cells are professional antigen-presenting cells that play a crucial role in initiating and regulating immune responses. In this review, we summarize the current progress of mRNA-based vaccines for gliomas, with a focus on recent advances in dendritic cell-based mRNA vaccines. We also discuss the feasibility and safety of mRNA-based clinical applications for gliomas.

The distribution and maturation of tertiary lymphoid structures can predict clinical outcomes of patients with gastric adenocarcinoma.

Introduction: Tertiary lymphoid structures (TLSs) are analogues of secondary lymphoid organs that contain various immune cells. The spatial distribution, maturation and composition of TLSs have differential effects on prognosis, and the roles of TLSs in gastric adenocarcinoma (GA) have not been revealed. Methods: Thus, we evaluated the prognostic value of TLSs in GA through analysis of bulk RNA sequencing(RNA-seq) data from public databases and validated our findings in tumour samples from the Fudan University Shanghai Cancer Center (FUSCC) cohort. The spatial distribution,maturation, and composition of TLSs in GA were analysed by reviewing H&E-stained sections and by multiplex immunofluorescence (mIF) staining. Results: We found that TLSs, especially TLSs with germinal centres (GCs) and TLSs located in the invasive margin (IM), were correlated with prolonged overall survival (OS). Second, analysis of public RNA-seq data showed that high dendritic cell (DC) scores were a favourable prognostic factor in GA patients with high scores for both TLSs and GCs. In the FUSCC cohort, DC-LAMP+ DCs weresignificantly enriched in IM-TLSs with GCs, suggesting a potential correlation between the tumour immune activation milieu and the DC abundance. Third, compared to that in TLSs without GCs, the proportion of FOXP3+CD8+ Treg cells was significantly decreased in IM-TLSs with GCs, and the percentage of PD1+CD20+ B cells was significantly increased in TLSs with GCs. Discussion: Our results demonstrate that the spatial arrangement and maturation of TLSs significantly affect prognosis and indicate that TLSs could be a new additional factor for histopathological evaluation.

Immunoglobulins: Mechanistic Approaches in Moderation of Various Inflammatory and Anti-Inflammatory Pathways.

Immunoglobulins (Ig) are proteins that help fight infections. IgG (IgG1, IgG2, IgG3, IgG4), IgM, IgA, IgD, and IgE are the five immunoglobulin subtypes that make up the majority of our immune system. Beneficial effects have been observed on the administration of Ig in diseases like Kawasaki, multiple myositis, chronic inflammatory demyelinating polyneuropathy (CIDP), and immune thrombocytopenia purpura (ITP). The Fc region, FcγRs, and FcRn of the IgG interact to provide both pro- and anti-inflammatory effects. IgM blocks immune-mediated inflammation using N-like glycans. It has been demonstrated that IgM demonstrates its antiinflammatory activity through IgM anti-leukocyte auto-antibodies (IgM-ALA). Since IgA is the second most prevalent and important Ig that operates on the primary objective in the immune system, which exhibits inhibitory signals in the body and generates inflammation in host cells, it plays a critical role in controlling mucosal homeostasis in the gastrointestinal (GI) tract. Additionally, it has been discovered that activating FcαRI boosts cytokine responses at different levels. IgD, a mysterious class of Ig once discovered, has a role in many disorders, including myeloma and Hodgkin's disease. The stability of IgD with development shows a different role, which has an advantage for the host's survival. IgE is mainly associated with many allergic diseases (food allergies), mediates type 1 responses, and has defenses against parasitic infections, which makes it an important parameter for monoclonal antibodies. Studies showed the possible roles of immunoglobulins, from which it came to light that immunoglobulins have their functions as agonists and antagonists in inflammation.

Tumor antigen presentation and the associated signal transduction during carcinogenesis.

Numerous developments have been achieved in the study and treatment of cancer throughout the decades that it has been common. After decades of research, about 100 different kinds of cancer have been found, each with unique subgroups within certain organs. This has significantly expanded our understanding of the illness. A mix of genetic, environmental, and behavioral variables contribute to the complicated and diverse process of cancer formation. Mutations, or changes in the DNA sequence, are crucial to the development of cancer. These mutations have the ability to downregulate the expression and function of Major Histocompatibility Complex class I (MHC I) and MHCII receptors, as well as activate oncogenes and inactivate tumor suppressor genes. Cancer cells use this tactic to avoid being recognized by cytotoxic CD8+T lymphocytes, which causes issues with antigen presentation and processing. This review goes into great length into the PI3K pathway, changes to MHC I, and positive impacts of tsMHC-II on disease-free survival and overall survival and the involvement of dendritic cells (DCs) in different tumor microenvironments. The vital functions that the PI3K pathway and its link to the mTOR pathway are highlighted and difficulties in developing effective cancer targeted therapies and feedback systems has also been mentioned, where resistance mechanisms include RAS-mediated oncogenic changes and active PI3K signalling.

The role of tryptophan metabolism and tolerogenic dendritic cells in maintaining immune tolerance: Insights into celiac disease pathogenesis.

BACKGROUND: In mammals, amino acid metabolism has evolved to control immune responses. Tryptophan (Trp) is the rarest essential amino acid found in food and its metabolism has evolved to be a primary regulatory node in the control of immune responses. Celiac disease (CeD) is a developed immunological condition caused by gluten intolerance and is linked to chronic small intestine enteropathy in genetically predisposed individuals. Dendritic cells (DCs), serving as the bridge between innate and adaptive immunities, can influence immunological responses in CeD through phenotypic alterations. OBJECTIVE: This review aims to highlight the connection between Trp metabolism and tolerogenic DCs, and the significance of this interaction in the pathogenesis of CeD. RESULTS: It is been recognized that various DC subtypes contribute to the pathogenesis of CeD. Tolerogenic DCs, in particular, are instrumental in inducing immune tolerance, leading to T-reg differentiation that helps maintain intestinal immune tolerance against inflammatory responses in CeD patients and those with other autoimmune disorders. T-regs, a subset of T-cells, play a crucial role in maintaining intestinal immunological homeostasis by regulating the activities of other immune cells. Notably, Trp metabolism, essential for T-reg function, facilitates T-reg differentiation through microbiota-mediated degradation and the kynurenine pathway. CONCLUSION: Therefore, alterations in Trp metabolism could potentially influence the immune response in CeD, affecting both the development of the disease and the persistence of symptoms despite adherence to a gluten-free diet.

Dendritic cells transfected with DNA constructs encoding CCR9, IL-10, and type II collagen demonstrate induction of immunological tolerance in an arthritis model.

Introduction: Restoring immune tolerance is a promising area of therapy for autoimmune diseases. One method that helps restore immunological tolerance is the approach using tolerogenic dendritic cells (tolDCs). In our study, we analyzed the effectiveness of using dendritic cells transfected with DNA constructs encoding IL-10, type II collagen, and CCR9 to induce immune tolerance in an experimental model of arthritis. Methods: Dendritic cell cultures were obtained from bone marrow cells of Balb/c mice. Dendritic cells (DCs) cultures were transfected with pmaxCCR9, pmaxIL-10, and pmaxCollagen type II by electroporation. The phenotype and functions of DCs were studied using enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Migration of electroporated DCs was assessed in vitro. Induction of antigen-collagen induced arthritis (ACIA) was carried out according to the protocol in Balb/c mice. DCs were then administered to ACIA mice. The development of arthritis was monitored by measuring paw swelling with a caliper at different time points. The immunological changes were assessed by analyzing the content of antibodies to type II collagen using enzyme immunoassay. Additionally, a histological examination of the joint tissue was conducted, followed by data analysis. The results are as follows: DCs were obtained, characterized by reduced expression of CD80, CD86, and H-2Db (MHC class I), increased expression of CCR9, as well as producing IL-10 and having migratory activity to thymus cells. Transfected DCs induced T-regulatory cells (T-reg) and increased the intracellular content of IL-10 and TGF-ß in CD4+T cells in their co-culture, and also suppressed their proliferative activity in response to antigen. The administration of tolDCs transfected with DNA constructs encoding type II collagen, IL-10, and CCR9 to mice with ACIA demonstrated a reduction in paw swelling, a reduction in the level of antibodies to type II collagen, and a regression of histological changes. Conclusion: The study presents an approach by which DCs transfected with DNA constructs encoding epitopes of type II collagen, IL-10 and CCR9 promote the development of antigen-specific tolerance, control inflammation and reduce the severity of experimental arthritis through the studied mechanisms: induction of T-reg, IL-10, TGF-ß.

Dendritic cell-related hub genes in head-and-neck squamous cell carcinoma: implications for prognosis and immunotherapy.

Background: In the context of head-and-neck squamous cell carcinoma (HNSCC), dendritic cells (DCs) assume pivotal responsibilities, acting as architects of antigen presentation and conductors of immune checkpoint modulation. In this study, we aimed to identify hub genes associated with DCs in HNSCC and explore their prognostic significance and implications for immunotherapy. Methods: Integrated clinical datasets from The Cancer Genome Atlas (TCGA)-HNSCC and GSE65858 cohorts underwent meticulous analysis. Employing weighted gene co-expression network analysis (WGCNA), we delineated candidate genes pertinent to DCs. Through the application of random survival forest and least absolute shrinkage and selection operator (LASSO) Cox's regression, we derived key genes of significance. Lisa (epigenetic Landscape In Silico deletion Analysis and the second descendent of MARGE) highlighted transcription factors, with Dual-luciferase assays confirming their regulatory role. Furthermore, immunotherapeutic sensitivity was assessed utilizing the Tumor Immune Dysfunction and Exclusion online tool. Results: This study illuminated the functional intricacies of HNSCC DC subsets to tailor innovative therapeutic strategies. We leveraged clinical data from the TCGA-HNSCC and GSE65858 cohorts. We subjected the data to advanced analysis, including WGCNA, which revealed 222 DC-related candidate genes. Following this, a discerning approach utilizing random survival forest analysis and LASSO Cox's regression unveiled seven genes associated with the prognostic impact of DCs, notably ACP2 and CPVL, associated with poor overall survival. Differential gene expression analysis between ACP2 + and ACP2 - DC cells revealed 208 differential expressed genes. Lisa analysis identified the top five significant transcription factors as STAT1, SPI1, SMAD1, CEBPB, and IRF1. The correlation between STAT1 and ACP2 was confirmed through quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Dual-luciferase assays in HEK293T cells. Additionally, TP53 and FAT1 mutations were more common in high-risk DC subgroups. Importantly, the sensitivity to immunotherapy differed among the risk clusters. The low-risk cohorts were anticipated to exhibit favorable responses to immunotherapy, marked by heightened expressions of immune system-related markers. In contrast, the high-risk group displayed augmented proportions of immunosuppressive cells, suggesting a less conducive environment for immunotherapeutic interventions. Conclusions: Our research may yield a robust DC-based prognostic system for HNSCC; this will aid personalized treatment and improve clinical outcomes as the battle against this challenging cancer continues.

ZnO nanoparticles induce melanoma-like lesions via recruiting dermal dendritic cells in barrier-damaged skin in mice.

ZnO nanoparticles (NPs) are used in skin treatments and cosmetics, the toxicity of long-term and continuous exposure to ZnO NPs is unknown. Mice with epidermal barrier dysfunction revealed melanoma-like lesions after continuous exposure to ZnO NPs. However, the effects of metallic NPs on the skin microenvironment and immune system remain poorly understood. Mice with epidermal barrier failure were given continuous exposure to ZnO NPs for 7 weeks. The malignant transformation of melanocytes was induced with ZnO NPs 2.5 µg/ml for 72 h exposure. The supernatant of the culture medium from dendritic cells after being exposed to 10 µg/ml ZnO NPs for 24 h was applied to melanocytes to explore the effect of recruitment of DCs. The expressure of ZnO NPs resulted in a tendency of malignant transformation of melanocytes, the recruitment of DCs induces this process by produce inflammatory factors such as TNF-α. These DC-produced inflammatory factors, which were induced by ZnO NP exposure, increased the production of matrix metalloproteinases in melanocytes and expedited the malignant transformation process. Our findings revealed that the disrupted cutaneous microenvironment by ZnO NPs penetrated directly promoted the malignant transformation of melanocytes, which process also indirectly enhanced by the TNF-αsecreted from the recruited DCs.

Myeloid C-type lectin receptors in host-pathogen interactions and glycan-based targeting.

Lectin-glycan interactions play a crucial role in the immune system. An important class of lectins in the innate immune system is myeloid C-type lectin receptors (CLRs). Myeloid CLRs act as pattern recognition receptors and are predominantly expressed by myeloid cells, such as macrophages, dendritic cells, and neutrophils. In innate immunity, CLRs contribute to self/non-self discrimination. While the recognition of pathogen-associated molecular patterns (PAMPs) by CLRs may contribute to a protective immune response, CLR engagement can also be exploited by pathogens for immune evasion. Since various CLRs act as endocytic receptors and trigger distinct signaling pathways in myeloid cells, CLR targeting has proven useful for drug/antigen delivery into antigen-presenting cells and the modulation of immune responses. This review covers recent discoveries of pathogen/CLR interactions and novel approaches for CLR targeting within the period of the past two years.

[Acute myeloid leukemia with mutated RUNX1 at the university hospitals of Strasbourg]. / Étude rétrospective des leucémies aiguës myéloïdes mutées RUNX1 aux hôpitaux ­universitaires de Strasbourg.

RUNX1 is essential during human hematopoiesis. Numerous RUNX1 deregulations have been described, including translocations and germline or somatic mutations. Recurrent de novo RUNX1 mutations in acute myeloid leukemias (AML) prompted the creation of a provisional entity of AML with mutated RUNX1 in the 2016 WHO. In addition, recent genomic studies underlined rare AML patients with plasmacytoid dendritic cell (pDC) expansion and high RUNX1 mutations frequency. To better characterized AML with RUNX1 mutations, we retrospectively investigated a cohort of 32 patients diagnosed at Strasbourg University Hospital. Detailed clinical and biological features were aggregated. The presence of a pDC contingent was assessed by cytology and flow cytometry. In our cohort, no common features were identified either in term of cytology, stage of leukemia arrest or mutational features. Based on our observations, mutated RUNX1 AMLs do not appear to be a distinct AML entity. The new 2022 WHO classification includes AML with mutated RUNX1 within AML myelodysplasia-related category. We also identified within our cohort a patient whose AML fulfilled AML-pDC criteria, a rare and newly included entity in the last WHO classification.

Classical dendritic cells contribute to hypoxia-induced pulmonary hypertension.

Pulmonary hypertension (PH) is a chronic and progressive disease with significant morbidity and mortality. It is characterized by remodeled pulmonary vessels associated with perivascular and intravascular accumulation of inflammatory cells. Although there is compelling evidence that bone marrow-derived cells, such as macrophages and T cells, cluster in the vicinity of pulmonary vascular lesions in humans and contribute to PH development in different animal models, the role of dendritic cells in PH is less clear. Dendritic cells' involvement in PH is likely since they are responsible for coordinating innate and adaptive immune responses. We hypothesized that dendritic cells drive hypoxic PH. We demonstrate that a classical dendritic cell (cDC) subset (cDC2) is increased and activated in wild-type mouse lungs after hypoxia exposure. We observe significant protection after the depletion of cDCs in ZBTB46 DTR chimera mice before hypoxia exposure and after established hypoxic PH. In addition, we find that cDC depletion is associated with a reduced number of two macrophage subsets in the lung (FolR2+ MHCII+ CCR2+ and FolR2+ MHCII+ CCR2-). We found that depleting cDC2s, but not cDC1s, was protective against hypoxic PH. Finally, proof-of-concept studies in human lungs show increased perivascular cDC2s in patients with Idiopathic Pulmonary Arterial Hypertension (IPAH). Our data points to an essential role of cDCs, particularly cDC2s, in the pathophysiology of experimental PH.

Monocyte Single-Cell Multimodal Profiling in Cardiovascular Disease Risk States.

BACKGROUND: Monocytes are a critical innate immune system cell type that serves homeostatic and immunoregulatory functions. They have been identified historically by the cell surface expression of CD14 and CD16. However, recent single-cell studies have revealed that they are much more heterogeneous than previously realized. METHODS: We utilized cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing to describe the comprehensive transcriptional and phenotypic landscape of 437 126 monocytes. RESULTS: This high-dimensional multimodal approach identified vast phenotypic diversity and functionally distinct subsets, including IFN-responsive, MHCIIhi (major histocompatibility complex class II), monocyte-platelet aggregates, as well as nonclassical, and several subpopulations of classical monocytes. Using flow cytometry, we validated the existence of MHCII+CD275+ MHCIIhi, CD42b+ monocyte-platelet aggregates, CD16+CD99- nonclassical monocytes, and CD99+ classical monocytes. Each subpopulation exhibited unique characteristics, developmental trajectories, transcriptional regulation, and tissue distribution. In addition, alterations associated with cardiovascular disease risk factors, including race, smoking, and hyperlipidemia were identified. Moreover, the effect of hyperlipidemia was recapitulated in mouse models of elevated cholesterol. CONCLUSIONS: This integrative and cross-species comparative analysis provides a new perspective on the comparison of alterations in monocytes in pathological conditions and offers insights into monocyte-driven mechanisms in cardiovascular disease and the potential for monocyte subpopulation targeted therapies.

Enhancing cancer immunotherapy with mannose mimicking glycopolymer nanoparticles induced activation of Dendritic cells.

Cancer immunotherapy leverages the immune system's inherent capacity to combat malignancies. However, effective stimulation of Dendritic cells (DCs) is challenging due to their limited distribution and the immune-suppressive tumor microenvironment. Thus, targeting mannose receptors, which are highly expressed on DCs, represents a promising strategy. This study investigates the development of mannose-based glycopolymer nanoparticles to induce activation of DCs through enhanced antigen presentation. A novel ABA-type triblock bioconjugated glycopolymer (PMn-b-PCL-b-PMn), which mimics mannose was synthesized. This polymer was further modified with Dihexadecyldimethylammonium bromide (DHDAB) to prepare cationic nanoparticles (CMNP) for gene delivery of pCMV-TRP2, an antigenic marker for both melanoma and glioblastoma. The immune response generated by CMNP and the CMNP-TRP2 polyplex was compared to an untreated control following subcutaneous injection in mice. Post-injection cytometric analysis revealed robust DC activation and increased T-cell populations in secondary lymphoid organs, including the spleen and lymph nodes. These findings suggest that CMNP can serve as a potent biomimicking vaccination vehicle against cancer, enhancing the immune response through targeted DCs activation.

TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function.

Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.

Inhibition of MARCKS phosphorylation attenuates of dendritic cell migration in a murine model of acute asthma.

BACKGROUND: MARCKS (myristoylated alanine-rich C kinase substrates) serves as a substrate for protein kinase C, residing in the plasma membrane while acts as an actin filament crosslinking protein. This investigation aims to elucidate phosphorylated MARCKS (p-MARCKS) levels and activity in allergic asthma patients and explore the therapeutic potential of peptide inhibitors targeting p-MARCKS in an acute mouse model of allergic asthma. METHODS: Immunohistochemistry and histology staining were employed on lung tissue slides to evaluate p-MARCKS expression and allergic asthma symptoms. Airway resistance was measured using invasive whole-body plethysmography. Flow cytometry detected lung dendritic cell migration, and migration/maturation assays were conducted on isolated murine bone marrow-derived dendritic cells (BM-DCs). RESULTS: Elevated p-MARCKS expression was observed in both human asthmatic tissues and animal models immunized with ovalbumin or Alternaria alternata. Remarkably, asthmatic individuals showed elevated high p-MARCKS expression in lung tissues. Intraperitoneal injection of the peptide MPS, targeting the MARCKS phosphorylation site domain, before allergen challenged, effectively suppressed MARCKS phosphorylation in murine lung tissues. MPS inhibited both in vivo and in vitro migration and maturation of dendritic cells (BM-DCs) and reduced Th2-related lymphocyte activation in bronchoalveolar lavage fluid (BALF). MPS pretreatment additionally suppressed all symptoms associated with allergic airway asthma, including a reduction in inflammatory cell influx, airway mucous cell metaplasia, and airway hyperreactivity. CONCLUSION: These findings suggest that phosphorylated MARCKS occurs in asthmatic lung tissue, and the inhibition of MARCKS phosphorylation by the MPS peptide reduces dendritic cell migration and Th2-related lymphocytes in the lungs in a murine model of acute asthma.

Mechanoimmune-Driven Backpack Sustains Dendritic Cell Maturation for Synergistic Tumor Radiotherapy.

Cell backpacks present significant potential in both therapeutic and diagnostic applications, making it essential to further explore their interactions with host cells. Current evidence indicates that backpacks can induce sustained immune responses. Our original objective was to incorporate a model antigen into the backpacks to promote dendritic cell maturation and facilitate antigen presentation, thereby inducing immune responses. However, we unexpectedly discovered that both antigen-loaded backpacks and empty backpacks demonstrated comparable abilities to induce dendritic cell maturation, resulting in nearly identical potency in T-cell proliferation. Our mechanistic studies suggest that the attachment of backpacks induces mechanical forces on dendritic cells via opening the PIEZO1 mechanical ion channel. This interaction leads to the remodeling of the intracellular cytoskeleton and facilitates the production of type I interferons by dendritic cells. Consequently, the mechano-immune-driven dendritic cell backpacks, when combined with radiotherapy, induce a robust antitumor effect. This research presents an avenue for leveraging mechanotransduction to enhance combination immunotherapeutic strategies, potentially leading to groundbreaking advancements in the field.