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16 pages, 10261 KB

Open AccessArticle

Specific Position of the Pulmonary Hilar Node in Cancer Immunity: Immunohistochemical and Morphometrical Study Using Lung Regional Nodes Obtained from Non-Small Cell Cancer Patients Without Metastasis

by Masaya Aoki, Go Kamimura, Aya Harada-Takeda, Toshiyuki Nagata, Gen Murakami and Kazuhiro Ueda

Lymphatics 2025, 3(2), 13; https://doi.org/10.3390/lymphatics3020013 - 21 May 2025

Cited by 2 | Viewed by 1217 | Correction

Abstract

Background: Nodal dendritic cells (DCs) and CD169-positive macrophages, possibly monocyte-derived, cross-present cancer antigens earlier in the proximal node than in the distal node. Methods: We performed immunohistochemical and morphometric analyses to show differences in the distributions of DC-SIGN-, CD68-, and CD169-positive cells in the paratracheal, subcarinal, and hilar nodes from 25 non-small cell lung cancer patients without metastasis. Results: CD169-positive and DC-SIGN-positive cells were colocalized in the subcapsular and paracortical sinuses, whereas CD68-positive, self-renewal alveolar macrophages were present in the medullary sinus. This complementary distribution was more evident in nodes other than hilar nodes. In hilar nodes, the proportion of CD68-positive macrophages usually exceeds 50%. Notably, the proportion of the overlapped cluster between CD169-positive cells and DC-SIGN-positive cells, which likely corresponds to the cross-presentation activity, was almost the same between the hilar and “next-upstream” node (i.e., the paratracheal node for the upper lobe and the subcarinal node for the lower lobe). Monocyte-derived cells occupied a significantly larger area in the hilar nodes of patients with upper lobe cancer than in patients with lower lobe cancer (p = 0.002–0.009). Conclusion: The specific site occupying the lung hilum with collateral vessels seemed to determine the hilar node composite cells. Full article

(This article belongs to the Special Issue New Lymphology Combined with Lymphatic Physiology, Innate Immunology, and Oncology)

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22 pages, 27185 KB

Open AccessArticle

Spatial Distribution of Non-Immune Cells Expressing Glycoprotein A Repetitions Predominant in Human and Murine Metastatic Lymph Nodes

by Loïc Rouaud, Louis Baudin, Marine Gautier-Isola, Pierre Van Meerbeeck, Emilie Feyereisen, Silvia Blacher, Nicolas van Baren, Frédéric Kridelka, Sophie Lucas and Agnes Noel

Cancers 2023, 15(23), 5621; https://doi.org/10.3390/cancers15235621 - 28 Nov 2023

Cited by 2 | Viewed by 2741

Abstract

Several types of cancer spread through the lymphatic system via the sentinel lymph nodes (LNs). Such LN-draining primary tumors, modified by tumor factors, lead to the formation of a metastatic niche associated with an increased number of Foxp3+ regulatory T cells (Tregs). These cells are expected to contribute to the elaboration of an immune-suppressive environment. Activated Tregs express glycoprotein A repetitions predominant (GARP), which binds and presents latent transforming growth factor beta 1 (TGF-β1) at their surface. GARP is also expressed by other non-immune cell types poorly described in LNs. Here, we mapped GARP expression in non-immune cells in human and mouse metastatic LNs. The mining of available (human and murine) scRNA-Seq datasets revealed GARP expression by blood (BEC)/lymphatic (LEC) endothelial, fibroblastic, and perivascular cells. Consistently, through immunostaining and in situ RNA hybridization approaches, GARP was detected in and around blood and lymphatic vessels, in (αSMA+) fibroblasts, and in perivascular cells associated with an abundant matrix. Strikingly, GARP was detected in LECs forming the subcapsular sinus and high endothelial venules (HEVs), two vascular structures localized at the interface between LNs and the afferent lymphatic and blood vessels. Altogether, we here provide the first distribution maps for GARP in human and murine LNs. Full article

(This article belongs to the Special Issue Endothelial Cells in Inflammation, Tissue Repair, Ageing and Cancer)

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18 pages, 3254 KB

Open AccessArticle

Immunomodulatory Responses of Subcapsular Sinus Floor Lymphatic Endothelial Cells in Tumor-Draining Lymph Nodes

by Eliane Sibler, Yuliang He, Luca Ducoli, Viviane Rihs, Patrick Sidler, Claudia Puig-Moreno, Jasmin Frey, Noriki Fujimoto, Michael Detmar and Lothar C. Dieterich

Cancers 2022, 14(15), 3602; https://doi.org/10.3390/cancers14153602 - 24 Jul 2022

Cited by 8 | Viewed by 4263

Abstract

Tumor-draining lymph nodes (LNs), composed of lymphocytes, antigen-presenting cells, and stromal cells, are highly relevant for tumor immunity and the efficacy of immunotherapies. Lymphatic endothelial cells (LECs) represent an important stromal cell type within LNs, and several distinct subsets of LECs that interact with various immune cells and regulate immune responses have been identified. In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize LECs from LNs draining B16F10 melanomas compared to non-tumor-draining LNs. Several upregulated genes with immune-regulatory potential, especially in LECs lining the subcapsular sinus floor (fLECs), were identified and validated. Interestingly, some of these genes, namely, podoplanin, CD200, and BST2, affected the adhesion of macrophages to LN LECs in vitro. Congruently, lymphatic-specific podoplanin deletion led to a decrease in medullary sinus macrophages in tumor-draining LNs in vivo. In summary, our data show that tumor-derived factors induce transcriptional changes in LECs of the draining LNs, especially the fLECs, and that these changes may affect tumor immunity. We also identified a new function of podoplanin, which is expressed on all LECs, in mediating macrophage adhesion to LECs and their correct localization in LN sinuses. Full article

(This article belongs to the Special Issue Tumor Vasculature and Immunity in Cancer)

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16 pages, 3528 KB

Open AccessArticle

Lymph-Derived Neutrophils Primarily Locate to the Subcapsular and Medullary Sinuses in Resting and Inflamed Lymph Nodes

by Jenny de Castro Pinho and Reinhold Förster

Cells 2021, 10(6), 1486; https://doi.org/10.3390/cells10061486 - 12 Jun 2021

Cited by 12 | Viewed by 5411

Abstract

Neutrophils are the first immune cells to be recruited from the blood to the tissue site of an infection or inflammation. It has been suggested that neutrophils are capable of migrating from the infected tissue via lymphatic vessels to the draining lymph nodes. However, it remains elusive as to which areas within the lymph nodes can be reached by such reversely migrating cells. To address this question, we applied a model for adoptive neutrophil transfer into the afferent lymphatic vessel that drains towards the popliteal lymph node in mice. We showed that resting and in vitro-activated neutrophils did not enter the lymph node parenchyma but localized primarily in the subcapsular and medullary sinuses. Within the medulla, neutrophils show random migration and are able to sense laser-induced sterile tissue injury by massively swarming to the damaged tissue site. Co-injected dendritic cells supported the entry of resting neutrophils into the lymph node parenchyma via the subcapsular sinus. In contrast, in vivo-activated adoptively transferred neutrophils were capable of migrating into the interfollicular areas of the lymph node. Collectively, the data presented here give further insights into the functional behavior of neutrophils within the lymph nodes. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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19 pages, 3885 KB

Open AccessFeature PaperArticle

Single-Cell Transcriptional Heterogeneity of Lymphatic Endothelial Cells in Normal and Inflamed Murine Lymph Nodes

by Eliane Sibler, Yuliang He, Luca Ducoli, Nadja Keller, Noriki Fujimoto, Lothar C. Dieterich and Michael Detmar

Cells 2021, 10(6), 1371; https://doi.org/10.3390/cells10061371 - 2 Jun 2021

Cited by 26 | Viewed by 7292

Abstract

The lymphatic system plays a crucial role in immunity and lymph nodes (LNs) undergo drastic remodeling during inflammation. Here, we used single-cell RNA sequencing to investigate transcriptional changes in lymphatic endothelial cells (LECs) in LNs draining naïve and inflamed skin. We found that subsets of LECs lining the different LN sinuses responded individually to skin inflammation, suggesting that they exert distinct functions under pathological conditions. Among the genes dysregulated during inflammation, we confirmed an up-regulation of CD200 in the LECs lining the subcapsular sinus floor with a possible function in immune regulation. Furthermore, by in silico analysis, we predicted numerous possible interactions of LECs with diverse immune cells in the LNs and found similarities in the transcriptional changes of LN LECs in different skin inflammation settings. In summary, we provide an in-depth analysis of the transcriptional landscape of LN LECs in the naïve state and in skin inflammation. Full article

(This article belongs to the Special Issue Mechanisms of Lymphatic Trafficking in Inflammation, Immunity and Metastasis)

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13 pages, 3209 KB

Open AccessCommunication

Computational Approach to 3D Modeling of the Lymph Node Geometry

by Alexey Kislitsyn, Rostislav Savinkov, Mario Novkovic, Lucas Onder and Gennady Bocharov

Computation 2015, 3(2), 222-234; https://doi.org/10.3390/computation3020222 - 22 May 2015

Cited by 33 | Viewed by 11474

Abstract

In this study we present a computational approach to the generation of the major geometric structures of an idealized murine lymph node (LN). In this generation, we consider the major compartments such as the subcapsular sinus, B cell follicles, trabecular and medullar sinuses, blood vessels and the T cell zone with a primary focus on the fibroblastic reticular cell (FRC) network. Confocal microscopy data of LN macroscopic structures and structural properties of the FRC network have been generated and utilized in the present model. The methodology sets a library of modules that can be used to assemble a solid geometric LN model and subsequently generate an adaptive mesh model capable of implementing transport phenomena. Overall, based on the use of high-resolution confocal microscopy and morphological analysis of cell 3D reconstructions, we have developed a computational model of the LN geometry, suitable for further investigation in studies of fluid transport and cell migration in this immunologically essential organ. Full article

(This article belongs to the Special Issue Computational Studies of Immune System Function)

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