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

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.

SUBMITTER: Sibler E

PROVIDER: S-EPMC9330828 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Multiphoton intravital microscopy (MP-IVM) is a powerful tool to image cells in vivo. Its application in immunology research has opened new horizons, allowing intravital imaging of leukocytes at the single-cell level. A transparent cornea is vital to retain vision. As an immune privileged site, a rapid innate response to foreign antigens is crucial in clearing opportunistic bacterial and viral pathogens, and minimizing collateral structural damage to the cornea. Furthermore, dissecting the mechanisms and preventing the immunological rejection process after corneal transplantation is imperative to retain sight. Therefore, understanding the underlying mechanisms behind corneal immunity, specifically the process of antigen presentation and adaptive immunity in the mandibular draining lymph nodes (dLNs) in vivo, is crucial. Attempts of intravital imaging of mandibular dLNs have yielded little success to date, due to breathing artifacts and the location that is difficult to access. Herein, we present the first MP-IVM mouse model of the mandibular dLNs, utilizing transgenic mice in which CD11c+ cells are fluorescently labeled. Furthermore, we demonstrate that CD11c-YFP+ cells are localized mainly in the parafollicular cortex (T cell zone) and subcapsular area and are sparsely distributed in the follicular region (B cell zone) of mandibular dLNs during steady state. A significant increase in host CD11c-YFP+ cell density is noted at 14 and 21 days following allogeneic corneal transplantation, compared to steady state (p < 0.05). Moreover, allogeneic corneal transplantation results in increased host-derived CD11c-YFP+ cell mean speed and displacement in mandibular dLNs, compared to steady state (p < 0.001). The meandering index, an index for directionality, is significantly increased after allogeneic corneal transplantation at both 14 and 21 days, compared to steady state (p < 0.001). Taken together, our study demonstrates the necessary methodology required for intravital multiphoton imaging of the mandibular dLNs, allowing visualization of spatiotemporal kinetics of immune cells in vivo, and provides a window into the corneal immune reflex arc. This technique will be a powerful tool to investigate the pathogenesis of ocular immune and inflammatory diseases.

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

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