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Purpose: To investigate the clinical significance and functional role of SIGLEC1-positive cells in non-small cell lungcancer (NSCLC) patients, focusing on their prognostic impact and therapeutic response. Methods: A multicenter retrospective cohort analysis was conducted, integrating data from multiple sources. Weanalyzed SIGLEC1 expression in NSCLC tissues, clinicopathological features, overall survival outcomes,chemotherapy responsiveness, and sensitivity to targeted therapies. We also developed a prognostic model basedon SIGLEC1 expression and clinical variables. Results: SIGLEC1 expression was significantly downregulated in NSCLC tissues, and the density of SIGLEC1-positivecells was inversely correlated with various clinicopathological features. Notably, patients with high infiltration ofSIGLEC1-positive cells exhibited significantly better overall survival outcomes. Furthermore, elevated SIGLEC1expression was associated with improved responsiveness to chemotherapy and demonstrated distinct patterns ofsensitivity to targeted therapies. A robust prognostic model was developed by integrating SIGLEC1 expression andclinical variables. Conclusions: This study highlighted the downregulation of SIGLEC1 in NSCLC tissues and its significant associationwith patient prognosis and therapeutic response. The findings suggested that SIGLEC1 played a critical role inmodulating the tumor immune microenvironment and has potential as both a prognostic biomarker and therapeutictarget in NSCLC. [ABSTRACT FROM AUTHOR]

Summary: Background: Breast cancer cells suppress the host immune system to efficiently invade the lymph nodes; however, the underlying mechanism remains incompletely understood. Here, we aimed to comprehensively characterise the effects of breast cancers on immune cells in the lymph nodes. Methods: We collected non-metastatic and metastatic lymph node samples from 6 patients with breast cancer with lymph node metastasis. We performed bulk transcriptomics, spatial transcriptomics, and imaging mass cytometry to analyse the obtained lymph nodes. Furthermore, we conducted histological analyses against a larger patient cohort (474 slices from 58 patients). Findings: The comparison between paired lymph nodes with and without metastasis from the same patients demonstrated that the number of CD169+ lymph node sinus macrophages, an initiator of anti-cancer immunity, was reduced in metastatic lymph nodes (36.7 ± 21.1 vs 7.3 ± 7.0 cells/mm2, p = 0.0087), whereas the numbers of other major immune cell types were unaltered. We also detected that the infiltration of CD169+ macrophages into metastasised cancer tissues differed by section location within tumours, suggesting that CD169+ macrophages were gradually decreased after anti-cancer reactions. Furthermore, CD169+ macrophage elimination was prevalent in major breast cancer subtypes and correlated with breast cancer staging (p = 0.022). Interpretation: We concluded that lymph nodes with breast cancer metastases have fewer CD169+ macrophages, which may be detrimental to the activity of anti-cancer immunity. Funding: JSPS KAKENHI (16H06279, 20H03451, 20H04842, 22H04925, 19K16770, and 21K15530, 24K02236), JSPS Fellows (JP22KJ1822), AMED (JP21ck0106698), JST FOREST (JPMJFR2062), Caravel, Co., Ltd, Japan Foundation for Applied Enzymology, and Sumitomo Pharma Co., Ltd. under SKIPS.

We studied the prognostic value of SIGLEC1 in colorectal cancer (CRC) using bioinformatics. SIGLEC1 exhibited differential expression between the tumor and control samples, and improved survival was observed in patients with increased SIGLEC1 expression. The univariate and multivariate analyses confirmed SIGLEC1 as an independent prognostic factor for CRC, based on which a nomogram was constructed for predicting survival in patients with CRC. Additionally, higher SIGLEC1 expression was correlated with increased immunological/stromal/ESTIMATE scores as well as immune cell infiltration and was strongly and positively associated with T helper cells and macrophages. Furthermore, significant positive correlations were observed between SIGLEC1 expression and inhibitory/coinhibitory immunological genes. Additionally, the TIDE results of patients with CRC showed that increased SIGLEC1 expression was related to poorer immunotherapeutic responses. In clinical samples from patients with CRC, a decrease in SIGLEC1 expression was noted compared to para-cancerous tissues and samples from patients who received Yiqi Huayu Jiedu Decoction (YHJD) treatment. The in vivo results indicated the superior efficacy of YHJD against CRC in inhibiting tumor metastasis. Our study demonstrates that SIGLEC1 serves as a prognostic factor for CRC, strongly linked to immune response, and can be modulated by YHJD, suggesting novel avenues for CRC treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Graves' disease (GD) is characterized by dysregulation of the i mmune system with aberrant immune cell function. However, there have been few previous studies on the role of monocytes in the pathology of GD. The object of this study was to investigate whether and how monocytes participate in GD pathology. CD14+ monocytes were isolated from untreated initial GD patients and healthy controls. Then, RNA-seq was performed to investigate changes in global mRNA expression in monocytes and found that type I interferon (IFN) signalling was among the top upregulated signalling pathways in GD monocytes. Type I IFN-induced sialic acid-binding immunoglobulin-like lectin1 (SIGLEC1) expression was significantly upregulated in un treated GD patients and correlated with thyroid parameters. Patient serum SIGLEC1 concentrations were reduced after anti-thyroid drug treatment. Inhibiting SIGLEC1 expression could inhibit proinflammatory cytokine (IL-1ß, IL-6, IL-8, IL-10 and M-CSF) expression in monocytes. In conclusion, our study suggested that type I IFN-mediated monocyte activation could have a deleterious effect on the pathogenesis of GD. These obser vations indicated that the inhibition of type I IFN-activated monocytes/macrophages could have a therapeutic effect on GD remission. [ABSTRACT FROM AUTHOR]

African swine fever virus (ASFV) is a complex large DNA enveloped virus that causes African swine fever (ASF) with a fatality rate of up to 100%, seriously threatening the global swine industry. Due to the strict cell tropism of ASFV, there is no effective in vitro cell line, which hinders its prevention and control. Herein, we analyzed genome-wide transcriptional profiles of ASFV-susceptible porcine alveolar macrophages (PAMs) and non-susceptible cell lines PK15 and 3D4-21, an found that PAM surface pattern recognition receptors (PRRs) were significantly higher and common differential genes were significantly enriched in phagocytosis compared with that observed in PK15 and 3D4-21 cell lines. Therefore, endocytosis functions of host cell surface PRRs may play key roles in ASFV infection in vitro. ASFV was found to be infective to PK15 and 3D4-21 cell lines overexpressing CD163 and Siglec1, and to the PK15S1-CD163 cell line stably expressing CD163 and Siglec1. However, the PK15 and 3D4-21 cell lines overexpressing CD163 or Siglec1 alone were not infectious. Simultaneous interference of CD163 and Siglec1 in PAMs with small interfering RNA (siRNA) significantly reduced the infectivity of ASFV. However, siRNA interference of CD163 and Siglec1 respectively did not affect ASFV infectivity. ASFV significantly inhibited IFN expression levels in PAMs and PK15S1-CD163 cells, but had no effect on PK15 and 3D4-21 cell lines. These results indicate that CD163 and Siglec1 are key receptors for ASFV-infected host cells, and both play a synergistic role in the process of ASFV infection. ASFV inhibits IFN expression in susceptible cells, thereby downregulating the host immune response and evading the immune mechanism. The discovery of the ASFV receptor provides novel ideas to study ASFV and host cell interactions, pathogenic mechanisms, development of receptor blockers, vaccine design, and disease resistance breeding.

CD169, also known as Siglec1 or Sialoadhesin (Sn), is a surface adhesion molecule on human myeloid cells. Being part of the Siglec family, it acts as a receptor for sialylated molecular structures, which are found among various pathogenic and non-pathogenic ligands. Recent data suggest that CD169 may represent a promising new biomarker in acute respiratory and non-respiratory viral infections, such as SARS-CoV-2, Respiratory syncytial virus (RSV) and Human immunodeficiency virus (HIV). Therein lies a great potential to sufficiently differentiate viral from bacterial infection, which has been an incessant challenge in the clinical management of infectious disease. CD169 equips myeloid cells with functions, reaching far beyond pathogen elimination. In fact, CD169 seems to crosslink innate and adaptive immunity by antigen presentation and consecutive pathogen elimination, embodying a substantial pillar of immunoregulation. Yet, our knowledge about the kinetics, mechanisms of induction, signaling pathways and its precise role in host-pathogen interaction remains largely obscure. In this review, we describe the role of CD169 as a potentially novel diagnostic biomarker for respiratory viral infection by evaluating its strengths and weaknesses and considering host factors that are involved in pathogenesis of virus infection. Finally, this brief review aims to point out shortcomings of available evidence, thus, guiding future work revolving the topic.

Objectives To evaluate and compare the diagnostic accuracy of SIGLEC1, a surrogate marker of type I IFN, with established biomarkers in an inception cohort of systemic lupus erythematosus (SLE). Methods SIGLEC1 was analysed by flow cytometry in 232 patients referred to our institution with suspected SLE between October 2015 and September 2020. Results SLE was confirmed in 76 of 232 patients (32.8 %) according to the 2019 EULAR/ACR classification criteria and their SIGLEC1 values were significantly higher compared with patients without SLE (P  <0.0001). A sensitivity of 98.7 %, a specificity of 82.1 %, a negative predictive value (NPV) of 99.2 % and a positive predictive value (PPV) of 72.8 % were calculated for SIGLEC1. Adjusted to the highest reported prevalence of SLE, the NPV and PPV were >99.9 % and 0.1 %, respectively. Using receiver operating characteristic (ROC) analysis and DeLong testing, the area under the curve (AUC) for SIGLEC1 (AUC = 0.95) was significantly higher than for ANA (AUC = 0.88, P  = 0.031), C3 (AUC = 0.83, P  = 0.001) and C4 (AUC = 0.83, P  = 0.002) but not for anti-dsDNA antibodies (AUC = 0.90, P  = 0.163). Conclusion IFN-I pathway activation is detectable in almost all newly diagnosed SLE patients. Thus, a negative test result for SIGLEC1 is powerful to exclude SLE in suspected cases. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (aGVHD) represents the rejection of the recipient's skin, gut, and liver tissues of an allogeneic hematopoietic stem cell transplantation (HSCT) by the donor T-cells. The onset of aGVHD is often rapid and its evolution is unpredictable. We undertook the single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) collected before aGVHD clinical onset in three patients and from one patient afterward. We used four HSCT recipients who remained free of aGVHD as controls. This analysis unveiled the presence of particular subpopulations of circulating monocytes and cytotoxic T cells (CTLs) in pre-aGVHD samples up to 18 days before clinical disease. These pre-aGVHD monocytes were characterized by an upregulation of the M2 polarity marker CD163 and the transmembrane protein SIGLEC1/CD169. At the same time, their CTL counterparts stood out for the upregulation of the CXCL10 receptor CXCR3 and the antigenic stimulation marker CD70. The occurrence of CD163/SIGLEC1 co-expressing monocytes upstream of aGVHD onset was validated using transcriptomic data from an independent cohort and by flow cytometry in additional blood samples. These findings point to potential early diagnostic tools and preventive therapeutic strategies for aGVHD., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons. [ABSTRACT FROM AUTHOR]

Background: To analyse the validity of membrane-bound SIGLEC1 (CD169) as a sensitive biomarker for monitoring disease activity in pediatric systemic lupus erythematosus (SLE). Methods: 27 children and adolescents with SLE were followed for a mean of 13.5 months. During consecutive routine visits SLEDAI-2k, C3, C4 and ds-DNA values were determined. Additionally, expression of SIGLEC1 on monocytes was determined by flow cytometry. The amount of PE-labelled CD169 mAb bound per monocyte was analyzed using QuantiBRITE™ PE tubes. Associations between biomarkers and the clinical course were investigated by regression analysis. Results: In general, SIGLEC1 expression is high on SLE-derived monocytes (mean 6 359 (SD 6 056) molecules/monocyte, cut-off 2 500 molecules/monocyte), all patients with newly diagnosed SLE exhibit elevated expression (mean 13366 (SD 7 750) molecules/monocyte). Changes (Δ) in SIGLEC1 levels during the clinical course is the only biomarker that significantly correlates with the change in SLEDAI-2k (betaST = 0.28, p = 0.001). At follow-up visit, a clinically important worsening was experienced by 47.6% of patients with a Δ SIGLEC1 > 2 151 molecules/cell (OR 5.31) and 72.4% with a Δ SIGLEC1 > 756 molecules/cell (OR 8.90). Conversely, 36.4% of patients with a Δ SIGLEC1 < -2 818 molecules/cell (OR 4.16, percentiles as cut-off criteria) and 50.0% of patients with a Δ SIGLEC1 < -1 370 molecules/cell (OR 3.55, application of Youden index) showed clinical improvement. SIGLEC1 expression correlates inversely with the amount of therapeutically applied hydroxychloroquine (p < 0.001). Conclusions: SIGLEC1 expression on monocytes is a sensitive biomarker for adjusting disease activity in childhood SLE and represents a promising and easily applicable tool for disease monitoring. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD), characterized by chronic inflammation, is a recognized global health crisis. Sialic acid-binding immunoglobulin-like lectin 1 (siglec1 or CD169), mainly expressed in macrophages and dendritic cells, is markedly upregulated after encountering pathogens or under acute/chronic inflammation conditions. However, it is rarely reported that whether siglec1 plays a role in the development of COPD. In this study, we found that siglec1 had higher expression in the lungs from COPD rats and in peripheral blood mononuclear cells (PBMCs) from COPD patients. Knockdown of siglec1 in vivo and in vitro dramatically decreased pro-inflammatory cytokines production in pulmonary macrophages and alleviated pulmonary inflammatory responses in COPD rats as well as inactivated nuclear factor kappa B (NF-κB) signaling. In addition, we identified a new microRNA, miR-195-5p, which has never explored in COPD, was lower expressed in COPD rats and PBMC of COPD patients, and could negatively modulate siglec1 expression in macrophages. Moreover, overexpression of miR-195-5p via miR-195-5p mimics in vitro and in vivo could significantly alleviate pro-inflammatory cytokines production in pulmonary macrophages and pulmonary inflammatory responses in COPD rats. Together, our findings suggested that miR-195-5p inhibited the development of COPD via targeting siglec1, which might become a therapeutic target to improve COPD. [ABSTRACT FROM AUTHOR]

Lymph nodes (LNs) are a common site of metastasis in solid cancers, and cutaneous melanomas show inherent properties of LN colonization. However, interactions between LN stroma and pioneer metastatic cells during metastatic colonization remain largely uncharacterized. Here we studied mice implanted with GFP-expressing melanoma cells to decipher early LN colonization events. We show that Siglec1-expressing subcapsular sinus (SCS) macrophages provide anchorage to pioneer metastatic cells. We performed in vitro co-culture to demonstrate that interactions between hypersialylated cancer cells and Siglec1 drive the proliferation of cancer cells. When comparing the transcriptome profile of Siglec1-interacting cancer cells against non-Siglec1-interacting cancer cells, we detected enrichment in positive regulators of cell cycle progression. Further, knockout of St3gal3 sialyltransferase compromised the metastatic efficiency of tumor cells by reducing α−2,3-linked sialylation. Thus, the interaction between Siglec1-expressing SCS macrophages and pioneer metastatic cells drives cell cycle progression and enables efficient metastatic colonization.

Unbiased proteomic profiling was performed toward the identification of biological parameters relevant in sIBM, thus giving hints about the pathophysiological processes and the existence of new reliable markers. For that purpose, skeletal muscle biopsies from 13 sIBM and 7 non-diseased control patients were analyzed with various methods, including liquid chromatography coupled to tandem mass spectrometry (four patients). Subsequent data analysis identified key molecules further studied in a larger cohort by qPCR, immunostaining, and immunofluorescence in situ. Proteomic signature of muscle biopsies derived from sIBM patients revealed the chaperone and cell surface marker CD74, the macrophage scavenger molecule CD163 and the transcription activator STAT1 to be among the highly and relevantly expressed proteins suggesting a significant contribution of immune cells among the myofibers expressing these markers. Moreover, in silico studies showed that 39% of upregulated proteins were involved in type I or mixed type I and type II interferon immunity. Indeed, further studies via immunohistochemistry clearly confirmed the prominent involvement of the key type I interferon signature-related molecules, ISG15 as well as IRF8 with MHC class II+ myofibers. Siglec1 colocalized with CD163+ macrophages and MHC class II molecules also co-localized with CD74 on macrophages. STAT1 co-localized with Siglec1+ macrophages in active myofibre myophagocytosis while STAT6 colocalized with endomysial macrophages. These combined results show involvement of CD74, CD163, and STAT1 as key molecules of macrophage activation being crucially involved in mixed and specific type I interferon, and interferon gamma associated-pathways in sIBM. On a more general note, these results also highlight the type of immune-interaction between macrophages and myofibers in the etiopathology of sIBM.

Unbiased proteomic profiling was performed toward the identification of biological parameters relevant in sIBM, thus giving hints about the pathophysiological processes and the existence of new reliable markers. For that purpose, skeletal muscle biopsies from 13 sIBM and 7 non-diseased control patients were analyzed with various methods, including liquid chromatography coupled to tandem mass spectrometry (four patients). Subsequent data analysis identified key molecules further studied in a larger cohort by q PCR, immunostaining, and immunofluorescence in situ. Proteomic signature of muscle biopsies derived from sIBM patients revealed the chaperone and cell surface marker CD74, the macrophage scavenger molecule CD163 and the transcription activator STAT1 to be among the highly and relevantly expressed proteins suggesting a significant contribution of immune cells among the myofibers expressing these markers. Moreover, in silico studies showed that 39% of upregulated proteins were involved in type I or mixed type I and type II interferon immunity. Indeed, further studies via immunohistochemistry clearly confirmed the prominent involvement of the key type I interferon signature-related molecules, ISG15 as well as IRF8 with MHC class II+ myofibers. Siglec1 colocalized with CD163+ macrophages and MHC class II molecules also co-localized with CD74 on macrophages. STAT1 co-localized with Siglec1+ macrophages in active myofibre myophagocytosis while STAT6 colocalized with endomysial macrophages. These combined results show involvement of CD74, CD163, and STAT1 as key molecules of macrophage activation being crucially involved in mixed and specific type I interferon, and interferon gamma associated-pathways in sIBM. On a more general note, these results also highlight the type of immune-interaction between macrophages and myofibers in the etiopathology of sIBM. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the role of two sialic acid binding immunoglobulin-like lectin (Siglec) family members SIGLECI and SIGLEC7 in circulating monocytes of patients with multiple sclerosis (MS). The study uses flow cytometry to determine the expression of SIGLECI and SIGLEC7. Results show that SIGLECI expression was significantly increased in MS patients compared with controlled group, while SIGLEC7 expression was up-regulated in blood monocytes.

Pathogens utilize various mechanisms to escape host immunological surveillance, break down different tissue barriers, and cause infection. Sialylation is an important surface modification of bacterial outer membrane components, especially the lipooligosaccharide of Gram-negative bacteria. It is widely involved in multiple microbe-host interactions, such as bacterial virulence regulation, host recognition, and immune evasion. There are some sialylation modifications on the lipooligosaccharide structure of Glaesserella parasuis ( G. parasuis ) virulent strains. However, the role of lipooligosaccharide sialylation modification in the process of G. parasuis infection and penetration of the porcine respiratory epithelial barrier is still unclear. In this study, we investigated the role and mechanism of lsgB -mediated lipooligosaccharide sialylation in G. parasuis invasion of the host respiratory epithelial barrier. Specifically, G. parasuis lsgB -mediated lipooligosaccharide sialylation and sialylated-lipooligosaccharide interacted with Siglec1 on porcine alveolar macrophages 3D4/21 and triggered the subsequent generation of TGFβ1 through Siglec1/Dap12/Syk/p38 signaling cascade. TGFβ1 decreased the tracheal epithelial tight junctions and the expression of extracellular adhesion molecule fibronectin, thus assisting G. parasuis invasion and entry to the respiratory epithelial barrier. Characterizing the potential effects and mechanisms of lipooligosaccharide sialylation-mediated TGFβ1 production would further expand our current knowledge on the pathogenesis of G. parasuis which will contribute to better prevention and control of G. parasuis infection in piglets.

The in vitro cell adhesion assay is a quantitative method for measuring selective cell adhesion to specific proteins. Traditionally, cell adhesion assays employ purified protein immobilized on a solid glass or plastic surface. Here, we describe a transient 293T cell transfection-based cell adhesion assay to study selective cell adhesion of a specific cell type to a protein of interest. In this protocol, 293T cells are transfected with a mammalian expression plasmid containing mSiglec1 cDNA or an empty plasmid as a mock control and are then cultured to form a monolayer. Subsequently, these Siglec1-expressing and mock-transfected 293T cell monolayers are used for cell adhesion assays with GFP-expressing B16F10 cells. The number of GFP + cancer cells adhering to each 293T monolayer is a quantitative mean to compare the selective adhesiveness of cancer cells to Siglec1. This method eliminates the need to express and purify the protein of interest to perform in vitro cell adhesion assays and can easily be performed with difficult-to-purify proteins while maintaining their native in situ structure., Competing Interests: Competing interestsThe authors declare no competing financial interests., (Copyright © The Authors; exclusive licensee Bio-protocol LLC.)

• PRRSV infection inhibits innate antiviral response in PAMs. • PRRSV infection enhances the level of pSn in PAMs. • Activation of pSn inhibits innate antiviral response in PAMs. • pSn1, pSn2, pSn3, pSn4 and pSn5 domains of pSn mediate the inhibition of innate antiviral response in PAMs. Porcine sialoadhesin (pSn) is a crucial porcine reproductive and respiratory syndrome virus (PRRSV) receptor mediating the attachment and internalization of virus into its major target cells, porcine alveolar macrophages (PAMs). However, the role of pSn in innate antiviral immune response has not yet been investigated. In this study, our results showed that PRRSV down-regulated significantly the mRNA levels of IFN-α, IFN-β, IFN-γ, IFN-λ1, IFN-λ3 and IFN-λ4 and up-regulated significantly the mRNA levels of IL-10 and pSn in infected PAMs in vitro , suggesting that PRRSV infection inhibited the transcription of innate antiviral cytokines in host cells. Our results also showed that selective activation of pSn down-regulated significantly the mRNA levels of IFN-α, IFN-β, IFN-γ, IFN-λ1, IFN-λ3, IFN-λ4 and TNF-α and up-regulated significantly the mRNA level of IL-10 in PAMs in vitro , suggesting that pSn signaling inhibited the transcription of innate antiviral cytokines. Further results showed that pSn1, pSn2, pSn3, pSn4 and pSn5 domains of pSn were responsible for the inhibition of levels of innate antiviral cytokines. In conclusion, our results suggested that pSn suppressed innate antiviral immune response by down-regulating the levels of innate antiviral cytokines in PAMs. It was possible that PRRSV-pSn interaction may suppress innate antiviral immune response to PRRSV infection by repressing the production of innate antiviral cytokines. [ABSTRACT FROM AUTHOR]

The roles of tumor-associated macrophages (TAMs) and circulating monocytes in human cancer are poorly understood. Here, we show that monocyte subpopulation distribution and transcriptomes are significantly altered by the presence of endometrial and breast cancer. Furthermore, TAMs from endometrial and breast cancers are transcriptionally distinct from monocytes and their respective tissue-resident macrophages. We identified a breast TAM signature that is highly enriched in aggressive breast cancer subtypes and associated with shorter disease-specific survival. We also identified an auto-regulatory loop between TAMs and cancer cells driven by tumor necrosis factor alpha involving SIGLEC1 and CCL8, which is self-reinforcing through the production of CSF1. Together these data provide direct evidence that monocyte and macrophage transcriptional landscapes are perturbed by cancer, reflecting patient outcomes. • Cancer alters circulating monocytic populations and their transcriptomes • Tumor-associated macrophages show tissue-specific programming • Tumor-associated macrophages' gene signature correlates with poor clinical outcome • Tumor-associated macrophages enhance cancer cells malignancy through CCL8 Cassetta et al. identify a breast cancer tumor-associated macrophage (TAM) transcriptome that is different from those of monocytes and tissue-resident macrophages, and which is associated with shorter disease-specific survival, and they demonstrate crosstalk between tumor cells and TAMs via SIGLEC1, CCL8, and CSF1. [ABSTRACT FROM AUTHOR]

Background: Tumor-derived antigens are captured by CD169 + (SIGLEC1 + ) sinus macrophages in regional lymph nodes (LNs), and are presented to effector cells inducing an anti-tumor immune response. Reduced CD169 expression in pre-metastatic regional LNs is associated with subsequent metastatic disease and a poor outcome in several tumor types, but if this is the case in prostate cancer has not been explored., Methods: CD169 expression was measured with immunohistochemistry in metastasis-free regional LNs from 109 prostate cancer patients treated with prostatectomy (January 1996 to April 2002). Possible associations of CD169 expression with PSA-relapse, prostate cancer death, Gleason score, and other clinical data were assessed using Kaplan-Meier survival- and Cox regression analysis. In addition, the Dunning rat prostate tumor model was used to examine CD169 expression in pre-metastatic LNs draining either highly metastatic MatLyLu- or poorly metastatic AT1-tumors., Results: In patients with low CD169 immunostaining in metastasis-free regional LNs, 8 of the 27 patients died from prostate cancer compared with only three of the 82 patients with high immunostaining (P < 0.001). CD169 expression in regional LNs was not associated with PSA-relapse. Rats with highly metastatic tumors had decreased CD169 immunoreactivity in pre-metastatic regional LNs compared with rats with poorly metastatic tumors., Conclusion: Low expression of CD169 in metastasis-free regional LNs indicates a reduced anti-tumor immune response. If verified in other studies, CD169 expression in regional LNs could, in combination with other factors, potentially be used as a marker of prostate cancer aggressiveness., (© 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.)

Objectives: Autoimmune congenital heart block (CHB) is associated with placental transcytosis of maternal autoantibodies directed against Ro/SS-A and La/SS-B. However, only about 2% of children born to mothers with the respective antibodies are affected, indicating that further risk factors exist, which are not yet fully understood. In this study, we investigated whether a maternal type I interferon (IFN) signature represents a risk factor for the development of CHB., Methods: Blood samples, clinical data and serological parameters from 9 women with CHB pregnancies, 14 pregnant women with antibodies against Ro/SS-A but without a CHB complication and another 30 healthy pregnant women as controls were studied. SIGLEC1 expression was measured by flow cytometry and was correlated to plasma IFN-α levels measured by ELISA, and IFN-γ-induced protein 10 (IP-10) levels measured by Bio-Plex technique., Results: Mothers of affected children had a significantly higher expression of SIGLEC1 (p=0.0034) and IFN-α (p=0.014), but not of IP-10 (p=0.14, all MWU) compared to mothers of unaffected children. SIGLEC1 and IFN-α expression were reduced by hydroxychloroquine and oral glucocorticoids., Conclusions: High expression of SIGLEC1 in pregnant women with autoantibodies against Ro/SS-A indicates an enhanced risk for CHB development, and these women may benefit especially from IFN-α directed therapy, for example with hydroxychloroquine., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Membrane-wrapped nanoparticles represent a versatile platform for utilizing specific lipid-receptor interactions, such as siallyllactose-mediated binding of the ganglioside GM3 to Siglec1 (CD169), for targeting purposes. The membrane wrap around the nanoparticles not only serves as a matrix to incorporate GM3 as targeting moiety for antigen-presenting cells but also offers unique opportunities for constructing a biomimetic surface from lipids with potentially protein-repellent properties. We characterize nonspecific protein adsorption (corona formation) to membrane-wrapped nanoparticles with core diameters of approximately 35 and 80 nm and its effect on the GM3-mediated targeting efficacy as a function of surface charge through combined in vitro and in vivo studies. The stability and fate of the membrane wrap around the nanoparticles in a simulated biological fluid and after uptake in CD169-expressing antigen-presenting cells is experimentally tested. Finally, we demonstrate in hock immunization studies in mice that GM3-decorated membrane-wrapped nanoparticles achieve a selective enrichment in the peripheral regions of popliteal lymph nodes that contain high concentrations of CD169-expressing antigen-presenting cells.

Next-generation nanoparticle-based drug delivery systems require the ability to target specific organelles or subcellular regions in selected target cells. Human immunodeficiency virus type I (HIV-1) particles are evolutionarily optimized nanocarriers that have evolved to avoid intracellular degradation and achieve enrichment at the synapse between mature dendritic cells (mDCs) and T cells by subverting cellular trafficking mechanisms. This study demonstrates that integration of the glycosphingolipid, GM3, in a membrane around a solid nanoparticle (NP) core is sufficient to recapitulate key aspects of the virus particle trafficking in mDCs. GM3-presenting artificial virus NPs (GM3-AVNs) accumulate in CD169(+) and CD81(+) nonlysosomal compartments in an actin-dependent process that mimics the sequestration of HIV-1. Live-cell optical tracking studies reveal a preferential recruitment and arrest of surface scanning CD4(+) T cells in direct vicinity to the AVN-enriched compartments. The formed mDC-T cell conjugates exhibit strong morphological similarities between the GM3-AVN-containing mDC-T cell synapse and the HIV-1 virological synapse, indicating that GM3-CD169 interactions alone are sufficient for establishing the mDC-T cell virological synapse. These results emphasize the potential of the GM3-AVN approach for providing therapeutic access to a key step of the host immune response--formation of the synaptic junction between an antigen-presenting cell (mDC) and T cells--for modulating and controlling immune responses.