Anticancer immune reaction and lymph node sinus macrophages: a review from human and animal studies.

Lymph nodes are secondary lymphoid organs localized throughout the body that typically appear as bean-like nodules. Numerous antigen-presenting cells, including dendritic cells and macrophages, that mediate host defense responses against pathogens, such as bacteria and viruses, reside within lymph nodes. To react to cancer cell-derived antigens in a variety of cancers, antigen-presenting cells induce cytotoxic T lymphocytes (CTLs). In relation to anticancer immune responses, macrophages in the lymph node sinus have been of particular interest because a number of studies involving both human specimens and animal models have reported that lymph node macrophages expressing CD169 play a key role in activating anticancer CTLs. Recent studies have indicated that dysfunction of lymph node macrophages potentially contributes to immune suppression in elderly patients and immunological "cold" tumors. Therefore, in anticancer therapy, the regulation of lymph node macrophages is a potentially promising approach.

CD169+ Skin Macrophages Function as a Specialized Subpopulation in Promoting Psoriasis-like Skin Disease in Mice.

Skin macrophages are critical to maintain and restore skin homeostasis. They serve as major producers of cytokines and chemokines in the skin, participating in diverse biological processes such as wound healing and psoriasis. The heterogeneity and functional diversity of macrophage subpopulations endow them with multifaceted roles in psoriasis development. A distinct subpopulation of skin macrophages, characterized by high expression of CD169, has been reported to exist in both mouse and human skin. However, its role in psoriasis remains unknown. Here, we report that CD169+ macrophages exhibit increased abundance in imiquimod (IMQ) induced psoriasis-like skin lesions. Specific depletion of CD169+ macrophages in CD169-ditheria toxin receptor (CD169-DTR) mice inhibits IMQ-induced psoriasis, resulting in milder symptoms, diminished proinflammatory cytokine levels and reduced proportion of Th17 cells within the skin lesions. Furthermore, transcriptomic analysis uncovers enhanced activity in CD169+ macrophages when compared with CD169- macrophages, characterized by upregulated genes that are associated with cell activation and cell metabolism. Mechanistically, CD169+ macrophages isolated from IMQ-induced skin lesions produce more proinflammatory cytokines and exhibit enhanced ability to promote Th17 cell differentiation in vitro. Collectively, our findings highlight the crucial involvement of CD169+ macrophages in psoriasis development and offer novel insights into the heterogeneity of skin macrophages in the context of psoriasis.

Sialic Acid-Siglec-E Interactions Regulate the Response of Neonatal Macrophages to Group B Streptococcus.

The mammalian Siglec receptor sialoadhesin (Siglec1, CD169) confers innate immunity against the encapsulated pathogen group B Streptococcus (GBS). Newborn lung macrophages have lower expression levels of sialoadhesin at birth compared with the postnatal period, increasing their susceptibility to GBS infection. In this study, we investigate the mechanisms regulating sialoadhesin expression in the newborn mouse lung. In both neonatal and adult mice, GBS lung infection reduced Siglec1 expression, potentially delaying acquisition of immunity in neonates. Suppression of Siglec1 expression required interactions between sialic acid on the GBS capsule and the inhibitory host receptor Siglec-E. The Siglec1 gene contains multiple STAT binding motifs, which could regulate expression of sialoadhesin downstream of innate immune signals. Although GBS infection reduced STAT1 expression in the lungs of wild-type newborn mice, we observed increased numbers of STAT1+ cells in Siglece-/- lungs. To test if innate immune activation could increase sialoadhesin at birth, we first demonstrated that treatment of neonatal lung macrophages ex vivo with inflammatory activators increased sialoadhesin expression. However, overcoming the low sialoadhesin expression at birth using in vivo prenatal exposures or treatments with inflammatory stimuli were not successful. The suppression of sialoadhesin expression by GBS-Siglec-E engagement may therefore contribute to disease pathogenesis in newborns and represent a challenging but potentially appealing therapeutic opportunity to augment immunity at birth.

Elevated unphosphorylated STAT1 and IRF9 in T and B cells of primary sjögren's syndrome: Novel biomarkers for disease activity and subsets.

OBJECTIVES: Autoreactive B cells and interferon (IFN) signature are hallmarks of primary sjögren's syndrome (pSS), but how IFN signaling pathways influence autoantibody production and clinical manifestations remain unclear. More detailed studies hold promise for improved diagnostic methodologies and personalized treatment. METHODS: We analyzed peripheral blood T and B cell subsets from 34 pSS patients and 38 healthy donors (HDs) at baseline and upon stimulation regarding their expression levels of type I and II IFN signaling molecules (STAT1/2, IRF1, IRF9). Additionally, we investigated how the levels of these molecules correlated with serological and clinical characteristics and performed ROC analysis. RESULTS: Patients showed elevated IFN pathway molecules, including STAT1, STAT2 and IRF9 among most T and B cell subsets. We found a reduced ratio of phosphorylated STAT1 and STAT2 in patients in comparison to HDs, although B cells from patients were highly responsive by increased phosphorylation upon IFN stimulation. Correlation matrices showed further interrelations between STAT1, IRF1 and IRF9 in pSS. Levels of STAT1 and IRF9 in T and B cells correlated with the IFN type I marker Siglec-1 (CD169) on monocytes. High levels of STAT1 and IRF9 within pSS B cells were significantly associated with hypergammaglobulinemia as well as anti-SSA/anti-SSB autoantibodies. Elevated STAT1 levels were found in patients with extraglandular disease and could serve as a biomarker for this subgroup (p < 0.01). Notably, IRF9 levels in T and B cells correlated with EULAR Sjögren's syndrome disease activity index (ESSDAI). CONCLUSION: Here, we provide evidence that in active pSS patients, enhanced IFN signaling incl. unphosphorylated STAT1 and STAT2 with IRFs entertain chronic T and B cell activation. Furthermore, increased STAT1 levels candidate as biomarker of extraglandular disease, while IRF9 levels can serve as biomarker for disease activity.

Lectin-Based Immunophenotyping and Whole Proteomic Profiling of CT-26 Colon Carcinoma Murine Model.

A murine colorectal carcinoma (CRC) model was established. CT26 colon carcinoma cells were injected into BALB/c mice's spleen to study the primary tumor and the mechanisms of cell spread of colon cancer to the liver. The CRC was verified by the immunohistochemistry of Pan Cytokeratin and Vimentin expression. Immunophenotyping of leukocytes isolated from CRC-bearing BALB/c mice or healthy controls, such as CD19+ B cells, CD11+ myeloid cells, and CD3+ T cells, was carried out using fluorochrome-labeled lectins. The binding of six lectins to white blood cells, such as galectin-1 (Gal1), siglec-1 (Sig1), Sambucus nigra lectin (SNA), Aleuria aurantia lectin (AAL), Phytolacca americana lectin (PWM), and galectin-3 (Gal3), was assayed. Flow cytometric analysis of the splenocytes revealed the increased binding of SNA, and AAL to CD3 + T cells and CD11b myeloid cells; and increased siglec-1 and AAL binding to CD19 B cells of the tumor-bearing mice. The whole proteomic analysis of the established CRC-bearing liver and spleen versus healthy tissues identified differentially expressed proteins, characteristic of the primary or secondary CRC tissues. KEGG Gene Ontology bioinformatic analysis delineated the established murine CRC characteristic protein interaction networks, biological pathways, and cellular processes involved in CRC. Galectin-1 and S100A4 were identified as upregulated proteins in the primary and secondary CT26 tumor tissues, and these were previously reported to contribute to the poor prognosis of CRC patients. Modelling the development of liver colonization of CRC by the injection of CT26 cells into the spleen may facilitate the understanding of carcinogenesis in human CRC and contribute to the development of novel therapeutic strategies.

The selection of animal models influences the assessment of anti-tumor efficacy: promising sialic acid-conjugate modified liposomes demonstrate remarkable therapeutic effects in diverse mouse strains.

Mice as a crucial tool for preclinical assessment of antineoplastic agents. The impact of physiological differences among mouse strains on the in vivo efficacy of antitumor drugs, however, has been significantly overlooked. Mononuclear phagocyte system (MPS) is the major player in clearance in vivo, and differences in MPS among different strains may potentially impact the effectiveness of antitumor preparations. Therefore, in this study, we employed conventional liposomes (CL-EPI) and SA-ODA modified liposomes (SAL-EPI) as model preparations to investigate the comprehensive tumor therapeutic effects of CL-EPI and SAL-EPI in KM, BALB/c, and C57BL/6 tumor-bearing mice. The results demonstrated significant variability in the efficacy of CL-EPI for tumor treatment across different mouse strains. Therefore, we should pay attention to the selection of animal models in the study of antitumor agents. SAL-EPI effectively targeted tumor sites by binding to Siglec-1 on the surface of peripheral blood monocytes (PBMs), and achieved good therapeutic effect in different mouse strains with little difference in treatment. The SA modified preparation is therefore expected to achieve a favorable therapeutic effect in tumor patients with different immune states through PBMs delivery (Siglec-1 was expressed in both mice and humans), thereby possessing clinical translational value and promising development prospects.

Sialic acid-decorated liposomes enhance the anti-cancer efficacy of docetaxel in tumor-associated macrophages.

Tumor-associated macrophages (TAMs) in the tumor microenvironment potentially enhance tumor growth and invasion through various mechanisms and are thus an essential factor in tumor immunity. The highly expressed siglec-1 receptors on the surfaces of TAMs are potential targets for cancer drug delivery systems. Sialic acid (SA) is a specific ligand for siglec-1. In this study, the sialic acid-polyethylene glycol conjugate (DSPE-PEG2000-SA) was synthesized to modify the surface of liposomes and target TAMs by interacting with the siglec-1 receptor. Three docetaxel (DTX)-loaded liposomes, conventional (DTX-CL), DSPE-PEG2000-coated (DTX-PL), and DSPE-PEG2000-SA-coated (DTX-SAPL) liposomes, were prepared, with a particle size of <100 nm, uniform polydispersity index (PDI) values, negative zeta potential, and % encapsulation efficiency (EE) exceeding 95 %. Liposomes showed high stability after 3 months of storage at 4 °C without significant changes in particle size, PDI, zeta potential, or % EE. DTX was released from liposomes according to the Weibull model, and DTX-SAPL exhibited more rapid drug release than other liposomes. In vitro studies demonstrated that DTX-SAPL liposome exhibited a higher uptake and cytotoxicity on RAW 264.7 cells (TAM model) and lower toxicity on NIH3T3 cells (normal cell model) than other formulations. The high cell uptake ability was demonstrated by the role of the SA-SA receptor. Biodistribution studies indicated a high tumor accumulation of surface-modified liposomal formulations, particularly SA-modified liposomes, showing high signal accumulation at the tumor periphery, where TAMs were highly concentrated. Ex vivo imaging showed a significantly higher accumulation of SA-modified liposomes in the tumor, kidney, and heart than conventional liposomes. In the anti-cancer efficacy study, DTX-SAPL liposomes showed effective inhibition of tumor growth and relatively low systemic toxicity, as evidenced by the tumor volume, tumor weight, body weight values, and histopathological analysis. Therefore, DSPE-PEG2000-SA-coated liposomes could be promising carriers for DTX delivery targeting TAMs in cancer therapy.

Sialoadhesin (CD169/Siglec-1) is an extended molecule that escapes inhibitory cis-interactions and synergizes with other macrophage receptors to promote phagocytosis.

Sialoadhesin (CD169/Siglec-1, Sn) is a macrophage receptor that interacts with sialic acids on both host cells and pathogens. It is a type 1 membrane protein with an unusually large number of 17 extracellular immunoglobulin (Ig)-like domains, made up of an N-terminal V-set domain that binds sialic acid and 16 adjacent C2-set domains. The potential importance of 17 Ig domains in Sn for mediating cellular interactions has not been investigated experimentally. In the present study, Chinese Hamster Ovary (CHO) cells were stably transfected with full-length or truncated forms of Sn. Using human red blood cells (RBC) as a model system, CHO cells expressing truncated forms of Sn with 4 or less Ig domains were unable to bind RBC in comparison to the full-length protein. Immunoelectron microscopy of the CHO cells indicated that full-length Sn extends ~ 33 nm from the plasma membrane compared with ~ 14 nm for a truncated form with 6 N-terminal Ig domains. Co-expresssion of Sn-expressing CHO cells with heavily glycosylated membrane proteins of differing predicted lengths resulted in selective modulation of Sn-dependent binding to RBC and supported the hypothesis that Sn has evolved 17 Ig domains to escape inhibitory cis-interactions. The functional significance of the extended length of Sn was demonstrated in experiments with macrophages showing that Sn synergizes with phagocytic receptors FcR and TIM-4 to strongly promote uptake of IgG-opsonized and eryptotic RBC respectively.

An Application of Tumor-Associated Macrophages as Immunotherapy Targets: Sialic Acid-Modified EPI-Loaded Liposomes Inhibit Breast Cancer Metastasis.

Breast cancer metastasis is an important cause of death in patients with breast cancer and is closely related to circulating tumor cells (CTCs) and the metastatic microenvironment. As the most infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs), which highly express sialic acid (SA) receptor (Siglec-1), are closely linked to tumor progression and metastasis. Furthermore, the surface of CTCs also highly expressed receptor (Selectin) for SA. A targeting ligand (SA-CH), composed of SA and cholesterol, was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SL) as an effective targeting delivery system. Liposomes were evaluated for characteristics, stability, in vitro release, cytotoxicity, cellular uptake, pharmacokinetics, tumor targeting, and pharmacodynamics. In vivo and in vitro experiments showed that EPI-SL enhanced EPI uptake by TAMs. In addition, cellular experiments showed that EPI-SL could also enhance the uptake of EPI by 4T1 cells, resulting in cytotoxicity second only to that of EPI solution. Pharmacodynamic experiments have shown that EPI-SL has optimal tumor inhibition with minimal toxicity, which can be ascribed to the fact that EPI-SL can deliver drugs to tumor based on TAMs and regulate TME through the depletion of TAMs. Our study demonstrated the significant potential of SA-modified liposomes in antitumor metastasis. Schematic diagram of the role of SA-CH modified EPI-loaded liposomes in the model of breast cancer metastasis.

Genetic modifications designed for xenotransplantation attenuate sialoadhesin-dependent binding of human erythrocytes to porcine macrophages.

The phenomenon of diminishing hematocrit after in vivo liver and lung xenotransplantation and during ex vivo liver xenoperfusion has largely been attributed to action by resident liver porcine macrophages, which bind and destroy human erythrocytes. Porcine sialoadhesin (siglec-1) was implicated previously in this interaction. This study examines the effect of porcine genetic modifications, including knockout of the CMAH gene responsible for expression of Neu5Gc sialic acid, on the adhesion of human red blood cells (RBCs) to porcine macrophages. Wild-type (WT) porcine macrophages and macrophages from several strains of genetically engineered pigs, including CMAH gene knockout and several human transgenes (TKO+hTg), were incubated with human RBCs and "rosettes" (≥3 erythrocytes bound to one macrophage) were quantified by microscopy. Our results show that TKO+hTg genetic modifications significantly reduced rosette formation. The monoclonal antibody 1F1, which blocks porcine sialoadhesin, significantly reduced rosette formation by WT and TKO+hTg macrophages compared with an isotype control antibody. Further, desialation of human RBCs with neuraminidase before addition to WT or TKO+hTg macrophages resulted in near-complete abrogation of rosette formation, to a level not significantly different from porcine RBC rosette formation on porcine macrophages. These observations are consistent with rosette formation being mediated by binding of sialic acid on human RBCs to sialoadhesin on porcine macrophages. In conclusion, the data predict that TKO+hTg genetic modifications, coupled with targeting of porcine sialoadhesin by the 1F1 mAb, will attenuate erythrocyte sequestration and anemia during ex vivo xenoperfusion and following in vivo liver, lung, and potentially other organ xenotransplantation.

CD169 (Siglec-1) as a Robust Human Cell Biomarker of Toll-Like Receptor 9 Agonist Immunotherapy.

Immunotherapy is a promising therapeutic area in cancer and chronic viral infections. An important component of immunotherapy in these contexts is the activation of innate immunity. Here we investigate the potential for CD169 (Siglec 1) expression on monocytes to serve as a robust biomarker for activation of innate immunity and, particular, as a proxy for IFN-α production. Specifically, we investigated the effects of Toll-like receptor 9 agonism with MGN1703 (lefitolimod) across experimental conditions ex vivo, in humanized mice, and in clinical trial participants. Ex vivo we observed that the percentage of classical monocytes expressing CD169 increased dramatically from 10% pre-stimulation to 97% 24 hrs after MGN1703 stimulation (p<0.0001). In humanized NOG mice, we observed prominent upregulation of the proportions of monocytes expressing CD169 after two doses of MGN1703 where 73% of classical monocytes were CD169 positive in bone marrow following MGN1703 treatment vs 19% in vehicle treated mice (p=0.0159). Finally, in a clinical trial in HIV-infected individuals receiving immunotherapy treatment with MGN1703, we observed a uniform upregulation of CD169 on monocytes after dosing with 97% of classical monocytes positive for CD169 (p=0.002). Hence, in this comprehensive evaluation ex vivo, in an animal model, and in a clinical trial, we find increases in the percentage of CD169 positive monocytes to be a reliable and robust biomarker of immune activation following TLR9 agonist treatment.

A Microbiota-Dependent Subset of Skin Macrophages Protects Against Cutaneous Bacterial Infection.

Microbiota is essential to the development and functional maturation of the immune system. The effects of the gut microbiota on myeloid cells remote from the gut, especially the skin remain unclear. Transcriptomic analysis revealed that type I interferon (IFN) signaling was down-regulated in the skin of germ-free mice compared to that in specific pathogen-free mice. The decrease in type I IFN signaling was closely related to the presence of microbiota and macrophage-specific marker CD169. The absence of CD169+ macrophages resulted in increased bacterial burden and impaired immune responses against Staphylococcus aureus skin infection. CD169+ macrophages mediated the recruitment of γδ T cells as well as the activation of γδ T cells via interleukin (IL)-23. Our findings demonstrate the role of the microbiota in establishment of a specific myeloid cell subset expressing CD169 in the skin and provide evidence of a specific mechanism by which this subset protects against bacterial skin infection.

CSF-1-induced DC-SIGN+ macrophages are present in the ovarian endometriosis.

BACKGROUND: Researchers have found that macrophages are the predominant cells in the peritoneal fluid (PF) of endometriosis patients. CSF-1 has been found to accumulate in the lesions and PF of endometriosis patients, and CSF-1 induces THP-1-derived macrophages to polarize toward a CD169+ DC-SIGN+ phenotype. Does the cytokine CSF-1 induce monocytes to differentiate into macrophages with a DC-SIGN+ phenotype in endometriosis? METHODS: The level of CSF-1 in the endometrium of control subjects, and the eutopic, and ectopic endometrium of endometriosis patients was evaluated by real-time polymerase chain reaction (qRT-PCR) and was determined by enzyme-linked immunosorbent assay (ELISA) in the PF of control and endometriosis patients. CSF-1 expression was examined with a MILLIPLEX MAP Mouse Cytokine/Chemokine Magnetic Bead Panel. DC-SIGN+ macrophages were detected by immunohistochemical staining of tissues and flow cytometric analysis of the PF of control subjects (N = 25) and endometriosis (N = 35) patients. The phenotypes and biological activities of CSF-1 -induced macrophages were compared in an in vitro coculture system with peripheral blood lymphocytes from control subjects. RESULTS: In this study, we found that the proportion of DC-SIGN+ CD169+ macrophages was higher in the abdominal immune microenvironment of endometriosis patients. CSF-1 was primarily secreted from ectopic lesions and peritoneum in mice with endometriosis. In addition, CSF-1 induced the polarization of macrophages toward a DC-SIGN+ CD169+ phenotype; this effect was abolished by the addition of an anti-CSF-1R antibody. CSF-1 induced the generation of DC-SIGN+ macrophages, leading to a depressed status of peripheral blood lymphocytes, including a high percentage of Treg cells and a low percentage of CD8+ T cells. Similarly, blockade with the anti-CSF-1R antibody abrogated this biological effect. CONCLUSIONS: This is the first study on the role of DC-SIGN+ macrophages in the immune microenvironment of endometriosis. Further study of the mechanism and biological activities of CSF-1-induced DC-SIGN+ macrophages will enhance our understanding of the physiology of endometriosis.

An adjuvant strategy enabled by modulation of the physical properties of microbial ligands expands antigen immunogenicity.

Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.

Naringenin potentiates anti-tumor immunity against oral cancer by inducing lymph node CD169-positive macrophage activation and cytotoxic T cell infiltration.

The CD169+ macrophages in lymph nodes are implicated in cytotoxic T lymphocyte (CTL) activation and are associated with improved prognosis in several malignancies. Here, we investigated the significance of CD169+ macrophages in oral squamous cell carcinoma (OSCC). Further, we tested the anti-tumor effects of naringenin, which has been previously shown to activate CD169+ macrophages, in a murine OSCC model. Immunohistochemical analysis for CD169 and CD8 was performed on lymph node and primary tumor specimens from 89 patients with OSCC. We also evaluated the effects of naringenin on two murine OSCC models. Increased CD169+ macrophage counts in the regional lymph nodes correlated with favorable prognosis and CD8+ cell counts within tumor sites. Additionally, naringenin suppressed tumor growth in two murine OSCC models. The mRNA levels of CD169, interleukin (IL)-12, and C-X-C motif chemokine ligand 10 (CXCL10) in lymph nodes and CTL infiltration in tumors significantly increased following naringenin administration in tumor-bearing mice. These results suggest that CD169+ macrophages in lymph nodes are involved in T cell-mediated anti-tumor immunity and could be a prognostic marker for patients with OSCC. Moreover, naringenin is a new potential agent for CD169+ macrophage activation in OSCC treatment.

Virus-Mimicking Polymer Nanoparticles Targeting CD169+ Macrophages as Long-Acting Nanocarriers for Combination Antiretrovirals.

Monosialodihexosylganglioside (GM3)-presenting lipid-coated polymer nanoparticles (NPs) that recapitulate the sequestration of human immunodeficiency virus-1 (HIV-1) particles in CD169+ virus-containing compartments (VCCs) of macrophages were developed as carriers for delivery and sustained release of a combination of two antiretrovirals (ARVs), rilpivirine (RPV) and cabotegravir (CAB). RPV and CAB were co-loaded into GM3-presenting lipid-coated polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA) NPs without loss in potency of the drugs. GM3-presenting PLA NPs demonstrated the most favorable release properties and achieved inhibition of HIV-1 infection of primary human macrophages for up to 35 days. Intracellular localization of GM3-presenting PLA NPs in VCCs correlated with retention of intracellular ARV concentrations and sustained inhibition of HIV-1 infection. This work elucidates the design criteria of lipid-coated polymer NPs to utilize CD169+ macrophages as cellular drug depots for eradicating the viral reservoir sites or to achieve long-acting prophylaxis against HIV-1 infection.

CD169+ macrophages in lymph node and spleen critically depend on dual RANK and LTbetaR signaling.

CD169+ macrophages reside in lymph node (LN) and spleen and play an important role in the immune defense against pathogens. As resident macrophages, they are responsive to environmental cues to shape their tissue-specific identity. We have previously shown that LN CD169+ macrophages require RANKL for formation of their niche and their differentiation. Here, we demonstrate that they are also dependent on direct lymphotoxin beta (LTß) receptor (R) signaling. In the absence or the reduced expression of either RANK or LTßR, their differentiation is perturbed, generating myeloid cells expressing SIGN-R1 in LNs. Conditions of combined haploinsufficiencies of RANK and LTßR revealed that both receptors contribute equally to LN CD169+ macrophage differentiation. In the spleen, the Cd169-directed ablation of either receptor results in a selective loss of marginal metallophilic macrophages (MMMs). Using a RANKL reporter mouse, we identify splenic marginal zone stromal cells as a source of RANKL and demonstrate that it participates in MMM differentiation. The loss of MMMs had no effect on the splenic B cell compartments but compromised viral capture and the expansion of virus-specific CD8+ T cells. Taken together, the data provide evidence that CD169+ macrophage differentiation in LN and spleen requires dual signals from LTßR and RANK with implications for the immune response.

Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. OBJECTIVE: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). METHODS: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C-like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). RESULTS: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57-/KLRGhi/CD161+/CD38- natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. CONCLUSION: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.

Metabolic installation of macrophage-recruiting glycan ligand on tumor cell surface for in vivo tumor suppression.

Synthetic probes that could direct immune cells against tumors are potential immunotherapeutics. We herein report in vivo tumor suppression via an intravenously injected abiotic sialic acid (TCCSia) that could be metabolically incorporated into tumor cell surface to yield of a high affinity ligand (TCCSiaα2,3-Gal) of Siglec-1 specifically expressed on macrophages. We observed marked suppression of pulmonary metastasis and subcutaneous tumor growth of B16F10 melanoma cells in mice with TCCSia, suggesting the utility of abiotic sialic acid to modulate tumor immunity via recruiting Siglec+ immune cells.

Prognostic value of CD169-positive macrophages in various tumors: a meta-analysis.

The study aimed to evaluate the prognostic value of CD169 expression in tumor-infiltrating macrophages from regional lymph nodes (RLN) in various tumors. In order to identify eligible articles, PubMed, EMBASE, Web of Science, and Cochrane Library were used to conduct a systematic search. Pooled hazard ratios (HRs) or odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were adopted to assess the relationship between CD169 expression and overall survival (OS) and clinicopathological characteristics. Ten studies, including eleven cohorts with 1699 patients, were enrolled. We found that high CD169+ expression in tumor-infiltrating macrophages from RLN was associated with a favorable OS (HR = 0.56, 95%CI: 0.39-0.79, P = 0.001). Subgroup analysis showed that high CD169+ expression had more predictive power in digestive system tumors (HR = 0.52, 95%CI: 0.42-0.67, <0.001). In addition, high CD169 expression was significantly linked with lymph node metastasis (OR = 0.66, 95%CI: 0.47-0.94, P = 0.020) and TNM stage (OR = 0.62, 95%CI: 0.48-0.80, P < 0.001). High CD169 expression in tumor-infiltrating macrophages from RLN was correlated with favorable survival outcome in patients with malignancies. CD169 may be a novel and effective prognostic marker, especially for digestive system tumors.