The mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm represents a clonal proliferation of plasmacytoid dendritic cells within myeloproliferative and myelodysplastic disorders. This entity was recently recognized as a distinct condition in the fifth edition of the World Health Organization classification of hematolymphoid tumors. It occurs in approximately 4.9% of acute myeloid leukemia cases. The pathogenic mechanisms underlying this proliferation and the role of these cells in disease progression remain poorly understood. Nevertheless, the plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia is related to distinct genetic abnormalities, worse prognosis, reduced overall survival, lower sensitivity to conventional acute myeloid leukemia therapies, and an increased risk of relapse. It also displays distinct immunophenotypic features compared to other types of mature plasmacytoid dendritic cell proliferation, raising questions about its classification and diagnostic criteria. This review provides a comprehensive overview of current knowledge regarding the plasmacytoid dendritic cell proliferation associated with acute myeloid leukemia, including terminology inconsistencies; the role of plasmacytoid dendritic cells in this entity; associated genetic alterations; immunophenotypic and morphological characteristics of blasts and plasmacytoid dendritic cells; clinical outcomes and prognostic impact; and therapeutic approaches and perspectives. Synthesizing current evidence may help improve disease recognition and highlight gaps in knowledge to guide future research.

The role of Plasmacytoid Dendritic Cells (pDCs) in Enterovirus-71 (EV71)-induced Hand, Foot, and Mouth Disease (HFMD) remains unclear. In this study, we investigated pDCs in severe HFMD patients infected with EV71. Flow cytometry revealed reduced pDC percentage in severe patients compared to healthy controls. In vitro, as EV71 replicated in pDCs, live cell numbers and levels of Interferon-alpha (IFN-a) and Interleukin (IL)-6 decreased, while IL-10 and Tumour Necrosis Factor-alpha (TNF-a) increased, particularly in critically ill patients. Notably, pDCs derived from critically ill patients exhibited significantly lower amplification rate and antiviral cytokine secretion compared to healthy controls. Analysis of the infection time course demonstrated that TLR7 expression rapidly increased at 6 h post-infection (h.p.i.), while its downstream signaling molecules reached higher levels by 24 h. TLR7 expression itself significantly decreased at 24 h.p.i. Pretreatment with the TLR7 inhibitor chloroquine (CQ) effectively suppressed the upregulation of TLR7. Concurrently, EV71 VP1 protein expression in the CQ-treated group remained at a moderate level throughout the time course, whereas it increased progressively in the untreated group. These findings suggest that EV71 may dynamically modulate the TLR7 pathway to evade innate immune recognition. In conclusion, EV71 may manipulate pDCs proliferation and cytokine secretion, evading the antiviral immune response, inducing cell tolerance, and promoting apoptosis. We speculate that EV71-induced inactivation of pDCs may contribute to disease deterioration.

IntroductionInflammatory breast cancer (IBC) is a rare invasive tumor and characterized by the formation of tumor emboli within dermal lymphatic vessels. The tumor microenvironment (TME) is a key factor in IBC aggressiveness, but its heterogeneity and intercellular role remain incompletely understood.MethodsWeighted gene coexpression network analysis (WGCNA) was performed to identify immune infiltration-associated genes. We also depicted cellular communication networks and specific ligand-receptor signaling pathways using the single-cell transcriptomics analysis of IBC and non-IBC samples. Finally, we verified the expression of key proteins by immunohistochemistry.ResultsThrough the intersection of WGCNA module genes and differentially expressed genes between pathological complete response and residual disease samples, GZMB was identified as hub gene which is related to immune infiltration and efficacy of neoadjuvant therapy in IBC. In IBC cohort, patients with high expression of GZMB harbored more immunosuppressive cells thus showed unfavorable prognosis compared with GZMB-low expression group (p<0.05). Subsequent to dimension reduction and clustering, 12 clusters were identified to construct the single-cell atlas between IBC and non-IBC samples. Cellular communication analysis unveiled the heterogeneity of cell communication in IBC. The proportion of immune cells was significantly lower than that of malignant epithelial cells in the cellular composition of IBC. Moreover, it indicated that SPP1 and plasmacytoid dendritic cells were specific in IBC and associated with an immunosuppressive microenvironment in IBC. Immunohistochemical analysis suggested that protein levels of GZMB and SPP1 tended to be higher in the samples from patients with residual disease compared to the patient achieving pathological complete response, though this observation is based on an extremely small sample size.DiscussionThis study identifies GZMB and SPP1 as potential immunosuppressive-related prognostic biomarkers in IBC patients, reveals the key role of plasmacytoid dendritic cells in remodeling of immunosuppressive microenvironment in IBC.

Background/Objectives: This study aimed to characterize dendritic cell (DC) heterogeneity, immune associations, and prognostic relevance across three TP53-mutated tumor entities-high-grade serous ovarian cancer (HGSOC), triple-negative breast cancer, and endometrial cancer-focusing on plasmacytoid DCs (pDCs) in HGSOC. Methods: RNA-sequencing and clinical data of 603 patients from The Cancer Genome Atlas were analyzed. DC subset abundance was assessed for cDC progenitor, conventional DC type 1 (cDC1), conventional DC type 2 (cDC2), plasmacytoid DC (pDC), and mature DC by marker gene signatures. Differences in DC scores across tumors were analyzed using Kruskal-Wallis. Survival analyses were performed using Kaplan-Meier and Cox regression. Spearman's correlation was used to determine associations between parameters. Results: HGSOC showed the lowest pDC abundance, yet high pDC scores were independently associated with shorter PFS (HR = 1.55, 95% CI: 1.05-2.27; p = 0.027), representing the only DC-subset-related prognostic signal observed across tumor types. pDCs correlated positively with neutrophils and negatively with monocytes, and pDCs, cDC2s, and cDC progenitors correlated inversely with TMB. No consistent link was found between pDC and TP53 mutation classes. However, tumors harboring specific TP53 mutations within established hotspot regions exhibited significantly lower pDC levels (p = 0.015). Conclusions: Our findings reveal distinct DC infiltration patterns and highlight the immunological vulnerability of TP53-mutated HGSOC. pDCs appear to exert a tumor-promoting, immune-evasive role, suggesting that DC function depends on their programming and tumor context. Selective targeting of DC subsets may offer novel therapeutic opportunities in TP53-mutated, low-TMB cancers.

Plasmacytoid dendritic cells (PDCs) signatures from integrated profiling predict AML prognosis and treatment response

The role of plasmacytoid dendritic cells (PDCs) has been studied in the cutaneous lupus erythematosus (CLE) to differentiate from their mimickers. We aimed to study the expression pattern of PDC markers in CLE subtypes, analyze their association with histopathological findings, and correlate them with disease activity in skin of color. This cross-sectional study included 115 newly diagnosed CLE cases [acute CLE = 41; discoid lupus erythematosus (DLE) = 72, subacute CLE = 2] from January 2022 to July 2024. Immunohistochemistry (IHC) for CD123, blood-derived dendritic cell antigen-2 (BDCA2), and human myxovirus resistance protein A (MXA) were performed in all cases. In DLE, the mean percentage of CD123 + cells in the superficial dermis (28.36 ± 2.584 vs. 23.05 ± 3.123) and deep dermis (14.83 ± 2.567 vs. 12.24 ± 3.377) were higher than in ACLE. No significant difference was noted in BDCA2 and MXA scores between DLE and ACLE. ACLE was marked by the absence of clustering ( P = 0.01, 73.2% vs. 44.4%), whereas DLE showed a significant presence of small clusters ( P = 0.01, 33.3% vs. 17.1%) and CD123 + cells at the dermoepidermal junction ( P = 0.05, 61.1% vs. 41.5%). A significant association was noted between CD123 + cells at specific locations and histopathological parameters. A linear trend was observed between positivity for CD123, BDCA2, and MXA with ordinal histopathological parameters . These markers did not show any significant correlations with disease activity scores. This is the largest comparative study to highlight the variability in the number, location, and clustering of PDCs among CLE subtypes, possibly relating to their clinical morphology and pathological features.

A small-molecule enhancer of STAT1 affects herpes simplex keratitis prognosis by mediating plasmacytoid dendritic cells migration through CXCR3/CXCL10.

To assess the impact of the IFIT3/TBK1 signalling pathway in activating plasmacytoid dendritic cells (pDCs) and its role in the development of SSc. Utilized single-cell RNA sequencing (scRNA-seq) and high-throughput transcriptome RNA sequencing to reveal the differential abundance of pDCs and the role of the key gene IFIT3 in SSc. Conducted in vitro cell experiments to evaluate the effect of IFIT3/TBK1 signalling pathway intervention on pDC activation cytokine release and fibroblast function. Constructed an IFIT3-/- mouse model using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing to assess the potential benefits of intervening in the IFIT3/TBK1 signalling pathway on skin and lung fibrosis in the SSc mouse model. The IFIT3/TBK1 signalling pathway plays a crucial role in activating pDCs, with IFIT3 acting as an upstream regulator of TBK1. Intervention in the IFIT3/TBK1 signalling pathway can inhibit pDC activation cytokine release and impact fibroblast function. The IFIT3-/- mouse model shows potential benefits of targeting the IFIT3/TBK1 signalling pathway in reducing skin and lung fibrosis in the SSc mouse model. This study provides new insights into potential therapeutic targets for SSc, highlighting the critical role of the IFIT3/TBK1 signalling pathway in SSc development. This study elucidates the pivotal role of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc). This study identified the key regulatory gene involved in systemic sclerosis (SSc) as IFIT3. This study has found that IFIT3 functions as an upstream regulatory factor, activating TBK1. This study provides Evidence of the regulatory effects of the IFIT3/TBK1 pathway on plasmacytoid dendritic cells (pDCs). This study validated the therapeutic potential using the IFIT3-/- mouse model.

Role of plasmacytoid dendritic cells in vascular dysfunction in mice with renovascular hypertension

Aims/Purpose: Prior work from our group has demonstrated a role for plasmacytoid dendritic cells (pDCs) in corneal nerve homeostasis. Herein, we sought to determine if pDC‐derived secretome could be used for the treatment of neuropathic corneal pain.Methods: The BDCA2‐DTR transgenic mice, in which pDCs can be selectively depleted result in subsequent nerve degeneration, were utilized for ex vivo electrophysiology studies. Animals were treated with pDC secretome drops, beginning 1 day after initial depletion. Electrophysiologic recordings were taken at day 3 post‐depletion analysed. A ciliary nerve ligation model of neuropathic corneal pain (NCP), was used to assess the therapeutic potential of pDC secretome. Spontaneous and evoked pain responses were assessed by palpebral opening measurements and hyperosmolar saline, respectively.Results: There was a significant reduction in cooling threshold following pDC depletion, which was rescued by pDC secretome treatment (26.85 ± 0.65°C vs. 29.52 ± 0.42°C; p &lt; 0.05), restoring the cooling threshold to control levels (29.21 ± 0.51). Furthermore, nerve terminal exhaustion was reduced following pDC depletion and rescued by pDC secretome treatment (0.55 ± 0.08 vs. 1.11 ± 0.10; p &lt; 0.01). Spontaneous pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (0.67 ± 0.03 vs. 0.85 ± 0.02; p &lt; 0.001). Similarly, evoked pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (30.25 ± 1.50 wipes/30 sec vs. 15.38 ± 1.29; p &lt; 0.0001).Conclusions: Herein, we demonstrate that pDC secretome restores normal functioning of corneal cold receptors. Importantly, in a translational model of NCP, pDC secretome treatment improved both spontaneous and evoked pain responses. Thus, pDC secretome is a viable therapeutic modality for further development and may hold promise in treatment of NCP and other corneal nerve related diseases.Reference1. Jamali A, Kenyon B, Ortiz G, Abou‐Slaybi A, Sendra VG, Harris DL, Hamrah P. Plasmacytoid Dendritic Cells in the Eye. Prog Retin Eye Res 2021; 80: 100877.2. Jamali A, Hu K, Sendra VG, Blanco T, Qazi Y, Zheng L, Turhan A, Hamrah P. Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis. Cell Rep 2020; 32: 108099.

Theiler's murine encephalomyelitis virus (TMEV) causes a chronic demyelinating disease similar to multiple sclerosis in mice. Although sialic acids have been shown to be essential for TMEV attachment to the host, the surface receptor has not been identified. While type I interferons play a pivotal role in the elimination of the chronic infectious Daniel (DA) strain, the role of plasmacytoid dendritic cells (pDCs) is controversial. We herein found that TMEV binds to conventional DCs but not to pDCs. A glycomics analysis showed that the sialylated N-glycan fractions were lower in pDCs than in conventional DCs, indicating that pDCs are not susceptible to TMEV infection due to the low levels of sialic acid. TMEV capsid proteins contain an integrin recognition motif, and dot blot assays showed that the integrin proteins bind to TMEV and that the viral binding was reduced in the desialylated αX β2 . αX β2 protein suppressed TMEV replication in vivo, and TMEV co-localized with integrin αM at the cell membrane and TLR 3 in the cytoplasm, suggesting that αM serves as the viral attachment and entry. These results show that the chronic encephalomyelitis virus utilizes sialylated integrins as cell surface receptors, leading to cellular tropism to evade pDC activation.

Abstract Despite advancement in surgical and medical management of pancreatic ductal adenocarcinoma (PDAC), this tumor type is currently the 3rd leading cause of cancer-related death in the United States and expected to become the 2nd by 2030. The development of ascites in PDAC patients generally indicates a poor prognosis although the reasons for this largely remain unknown. The exact mechanism of peritoneal spread of the cancer is still largely unknown. Herein, we collected and processed sterile ascites samples of 20 PDAC samples from 19 patients and performed single-cell RNA-seq analysis. Sixteen ascites samples were obtained from abdominal paracentesis and two cases in the postmortem period. For one patient ascites was collected both pre and postmortem. All but one patient received chemotherapy prior to ascites collection. Routine clinical cytology evaluation of ascites samples from 17 patients indicated it was malignant in 11 patients and nonmalignant in six patients. All ascites samples were purified by gradient centrifuge using Ficoll-Paque Plus to remove erythrocytes and necrotic debris. DAPI negative and Calcein positive cells were selected to enrich live cells from the cell suspension by flow sorting. We adopted the 10x Genomics Chromium Single Cell Gene Expression platform for single-cell RNA-seq library preparation. Scanpy was used for computational analysis of expression data after Cell Ranger pipelines. After QC check, normalization and doublet elimination, a total of 248,263 cells were analyzed. UMAP projection accurately clustered cells from each patient. Cell type annotation identified large numbers of immune cells compared to cancer cells and mesothelial cells with the most dominant population being macrophages. A subpopulation (0.23% of all cells) representing plasmacytoid dendritic cells was also found. Cancer cells were detected in twelve samples whereas no cancer cells were detected in eight samples after exhaustive marker gene exploration, and these findings largely matched the clinical diagnoses for each sample. In the ongoing period we will compare malignant versus non-malignant ascites by differential gene expression analysis, gene set enrichment analysis and trajectory inference to determine a) the extent the immunological clusters are enriched in malignant versus benign ascites, b) the distinct phenotypes and cell states of PDAC cells in immune rich versus immune poor ascites, c) role of plasmacytoid dendritic cells or mesothelial cells contribution to formation of malignant ascites. We believe our results will shed light on the dynamics of ascites formation and in turn identify novel targets for intervention. Citation Format: Shigeaki Umeda, Elias- Ramzey Karnoub, Etay Ziv, Jean Wu, Cristian Cruz, Wungki Park, Fiyinfolu Balogun, Alejandro Jiménez- Sánchez, Ronan Chaligné, Eileen M. O'Reilly, Christine A. Iacobuzio- Donahue. A single cell landscape of malignant pancreas cancer ascites [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1241.

Systemic sclerosis (SSc) is a debilitating autoimmune disease that affects multiple systems. It is characterized by immunological deregulation, functional and structural abnormalities of small blood vessels, and fibrosis of the skin, and, in some cases, internal organs. Fibrosis has a devastating impact on a patient's life and lung fibrosis is associated with high morbimortality. Several immune populations contribute to the progression of SSc, and plasmacytoid dendritic cells (pDCs) have been identified as crucial mediators of fibrosis. Research on murine models of lung and skin fibrosis has shown that pDCs are essential in the development of fibrosis, and that removing pDCs improves fibrosis. pDCs are a subset of dendritic cells (DCs) that are specialized in anti-viral responses and are also involved in autoimmune diseases, such as SSc, systemic lupus erythematosus (SLE) and psoriasis, mostly due to their capacity to produce type I interferon (IFN). A type I IFN signature and high levels of CXCL4, both derived from pDCs, have been associated with poor prognosis in patients with SSc and are correlated with fibrosis. This review will examine the recent research on the molecular mechanisms through which pDCs impact SSc.

Plasmacytoid dendritic cells (pDCs) are a special subtype of dendritic cells with the morphology of plasma cells. pDCs produce massive amounts of type I interferon (IFN-I), which was originally found to play an extremely pivotal role in antiviral immunity. Interestingly, accumulated evidence indicates that pDCs can also play an important role in tumorigenesis. In the human body, most of the IFN-α is secreted by activated pDCs mediated by toll-like receptor (TLR) stimulation. In many types of cancer, tumors are infiltrated by a large number of pDCs, however, these pDCs exhibit no response to TLR stimulation, and reduced or absent IFN-α production. In addition, tumor-infiltrating pDCs promote recruitment of regulatory T cells (Tregs) into the tumor microenvironment, leading to immunosuppression and promoting tumor growth. In this review, we discuss recent insights into the development of pDCs and their roles in a variety of malignancies, with special emphasis on the basic mechanisms.

P-086: Quantitative seroproteomics analysis of Multiple Myeloma patients treated with Tagraxofusp, a novel CD123-directed targeted therapy, identifies novel cytokine-mediated mechanism of action

The literature review is devoted to the discussion of the role of respiratory viral infections in the development of exacerbations of bronchial asthma. Despite significant advances in the development of new approaches and means of treating bronchial asthma, an insufficient level of control of the disease remains, one of the consequences of which is an exacerbation of asthma, which causes significant damage both to the health of patients and leads to high costs of the healthcare system for treatment. The article provides data on the leading causal role in the development of exacerbations of bronchial asthma in children, as well as adult respiratory viruses, among which rhinoviruses are most often detected during exacerbations, especially rhinovirus C. Based on the research results, the mechanisms of predisposition of patients with bronchial asthma to virus-induced exacerbations are considered in detail., including at the gene level, associated both with the suppression of the production of cytokines suppressing the replication and spread of viruses, in particular alpha-interferon, and the stimulation of the production of T2 cytokines, such as IL5. An important role in the development of asthma exacerbations in viral infections of allergic sensitization is indicated, the role of allergen-specific IgE antibodies in the pathogenesis of asthma exacerbations caused by viruses is discussed. The data on the role of plasmacytoid dendritic cells in the formation of the pathological process in virusinduced exacerbations in patients with atopic bronchial asthma are presented. The results of studies obtained both in real clinical practice and in experimental rhinovirus infection in patients with asthma, testifying to the high therapeutic efficacy of the preparation of monoclonal antibodies against IgE – omalizumab – in the prevention and treatment of exacerbations of bronchial asthma caused by respiratory viruses are presented.

A High Throughput Quantitative Seroproteomics Analysis of Multiple Myeloma Patients on Tagraxofusp Therapy Identifies Novel Cytokine-Assisted Mechanism of Action

The Covid-19 pandemic represents an unsolved problem which has caused numerous fatalities. At the present time, there is no vaccination available or curative therapy. However, recent reports suggest that SARS-CoV2 acts upon its functional receptor ACE2 inducing a variety of deleterious effects such as inflammation, endothelial dysfunction, microangiopathy, myocarditis, thrombosis and myocardial infarction. The details of the SARS-CoV2 -ACE2 interaction are poorly understood and most of the hypothesis related to this are based on the extrapolation of previous research focusing on ACE2 as a receptor for SARS-CoV. Considering the similarities between SARS-CoV2 and SARS-CoV we have conducted e physiopathological analysis focusing on the key pathogenic role of ACE2 as a functional receptor for SARS-CoV2. In this context, we have identified several potential therapeutic targets which should be further evaluated in patients with Covid-19. It is likely that an efficient therapy for Covid-19 will be revealed by research investigating the binding of viral spike S protein to ACE2, and the immunological response determined by SARS-CoV2-ACE2 interaction, including the anti-viral role of plasmacytoid dendritic cells and anti-inflammatory reprogramming of macrophages. &nbsp;

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. An unbalanced immune response, characterized by a weak production of type I interferons (IFN-Is) and an exacerbated release of proinflammatory cytokines, contributes to the severe forms of the disease. SARS-CoV-2 is genetically related to SARS-CoV and Middle East respiratory syndrome-related coronavirus (MERS-CoV), which caused outbreaks in 2003 and 2013, respectively. Although IFN treatment gave some encouraging results against SARS-CoV and MERS-CoV in animal models, its potential as a therapeutic against COVID-19 awaits validation. Here, we describe our current knowledge of the complex interplay between SARS-CoV-2 infection and the IFN system, highlighting some of the gaps that need to be filled for a better understanding of the underlying molecular mechanisms. In addition to the conserved IFN evasion strategies that are likely shared with SARS-CoV and MERS-CoV, novel counteraction mechanisms are being discovered in SARS-CoV-2–infected cells. Since the last coronavirus epidemic, we have made considerable progress in understanding the IFN-I response, including its spatiotemporal regulation and the prominent role of plasmacytoid dendritic cells (pDCs), which are the main IFN-I–producing cells. While awaiting the results of the many clinical trials that are evaluating the efficacy of IFN-I alone or in combination with antiviral molecules, we discuss the potential benefits of a well-timed IFN-I treatment and propose strategies to boost pDC-mediated IFN responses during the early stages of viral infection.

Decreased circulating levels of plasmacytoid dendritic cells in women with early-onset preeclampsia