| 1. |
- van Hooren, Luuk, et al.
(författare)
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Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma.
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas are brain tumors characterized by an immunosuppressive microenvironment. Immunostimulatory agonistic CD40 antibodies (αCD40) are in clinical development for solid tumors, but are yet to be evaluated for glioma. Here, we demonstrate that systemic delivery of αCD40 in preclinical glioma models induces the formation of tertiary lymphoid structures (TLS) in proximity of meningeal tissue. In treatment-naïve glioma patients, the presence of TLS correlates with increased T cell infiltration. However, systemic delivery of αCD40 induces hypofunctional T cells and impairs the response to immune checkpoint inhibitors in pre-clinical glioma models. This is associated with a systemic induction of suppressive CD11b+ B cells post-αCD40 treatment, which accumulate in the tumor microenvironment. Our work unveils the pleiotropic effects of αCD40 therapy in glioma and reveals that immunotherapies can modulate TLS formation in the brain, opening up for future opportunities to regulate the immune response.
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| 2. |
- Bekkhus, Tove, et al.
(författare)
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Automated detection of vascular remodeling in human tumor draining lymph nodes by the deep learning tool HEV-finder
- 2022
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Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 258:1, s. 4-11
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Tidskriftsartikel (refereegranskat)abstract
- Vascular remodeling is common in human cancer and has potential as future biomarkers for prediction of disease progression and tumor immunity status. It can also affect metastatic sites, including the tumor-draining lymph nodes (TDLNs). Dilation of the high endothelial venules (HEVs) within TDLNs has been observed in several types of cancer. We recently demonstrated that it is a premetastatic effect that can be linked to tumor invasiveness in breast cancer. Manual visual assessment of changes in vascular morphology is a tedious and difficult task, limiting high-throughput analysis. Here we present a fully automated approach for detection and classification of HEV dilation. By using 12,524 manually classified HEVs, we trained a deep-learning model and created a graphical user interface for visualization of the results. The tool, named the HEV-finder, selectively analyses HEV dilation in specific regions of the lymph nodes. We evaluated the HEV-finder's ability to detect and classify HEV dilation in different types of breast cancer compared to manual annotations. Our results constitute a successful example of large-scale, fully automated, and user-independent, image-based quantitative assessment of vascular remodeling in human pathology and lay the ground for future exploration of HEV dilation in TDLNs as a biomarker.
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| 3. |
- Stanczuk, Lukas, et al.
(författare)
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cKit Lineage Hemogenic Endothelium-Derived Cells Contribute to Mesenteric Lymphatic Vessels
- 2015
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 10:10, s. 1708-1721
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Tidskriftsartikel (refereegranskat)abstract
- Pathological lymphatic diseases mostly affect vessels in specific tissues, yet little is known about organ-specific regulation of the lymphatic vasculature. Here, we show that the vascular endothelial growth factor receptor 3 (VEGFR-3)/p110 alpha PI3-kinase signaling pathway is selectively required for the formation of mesenteric lymphatic vasculature. Using genetic lineage tracing, we demonstrate that part of the mesenteric lymphatic vasculature develops from cKit lineage cells of hemogenic endothelial origin through a process we define as lymphvasculogenesis. This is contrary to the current dogma that all mammalian lymphatic vessels form by sprouting from veins. Our results reveal vascular-bed-specific differences in the origin and mechanisms of vessel formation, which may critically underlie organ-specific manifestation of lymphatic dysfunction in disease. The progenitor cells identified in this study may be exploited to restore lymphatic function following cancer surgery, lymphedema, or tissue trauma.
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| 4. |
- Arroz-Madeira, Silvia, et al.
(författare)
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Lessons of Vascular Specialization From Secondary Lymphoid Organ Lymphatic Endothelial Cells
- 2023
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Ingår i: Circulation Research. - : Wolters Kluwer. - 0009-7330 .- 1524-4571. ; 132:9, s. 1203-1225
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Forskningsöversikt (refereegranskat)abstract
- Secondary lymphoid organs, such as lymph nodes, harbor highly specialized and compartmentalized niches. These niches are optimized to facilitate the encounter of naive lymphocytes with antigens and antigen-presenting cells, enabling optimal generation of adaptive immune responses. Lymphatic vessels of lymphoid organs are uniquely specialized to perform a staggering variety of tasks. These include antigen presentation, directing the trafficking of immune cells but also modulating immune cell activation and providing factors for their survival. Recent studies have provided insights into the molecular basis of such specialization, opening avenues for better understanding the mechanisms of immune-vascular interactions and their applications. Such knowledge is essential for designing better treatments for human diseases given the central role of the immune system in infection, aging, tissue regeneration and repair. In addition, principles established in studies of lymphoid organ lymphatic vessel functions and organization may be applied to guide our understanding of specialization of vascular beds in other organs.
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| 5. |
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| 6. |
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| 7. |
- Bekkhus, Tove, et al.
(författare)
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Remodeling of the Lymph Node High Endothelial Venules Reflects Tumor Invasiveness in Breast Cancer and is Associated with Dysregulation of Perivascular Stromal Cells
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Tumor draining lymph nodes (TDLNs) are the most common metastatic sites in human cancer but are also essential sites for induction of tumor immunity. How different types of primary tumors affect the anti-tumor immune response in the LNs is not fully understood. By analyzing biobank tissue from breast cancer patients, we demonstrate that invasive breast cancer induce dramatic pre-metastatic LN changes affecting the structure and function of the specialized LN vasculature and associated stromal cells, required for recruitment of T-lymphocytes into the LNs. These changes could not be seen in patients with non-invasive breast cancer and provide new insights of how invasive tumors can disrupt essential functions within the immune system. The data also shows promise of LN stromal and vascular changes as possible future biomarkers for prediction of disease progression in human cancer. The tumor-draining lymph nodes (TDLNs) are primary sites for induction of tumor immunity. They are also common sites of metastasis, suggesting that tumor-induced mechanisms can subvert anti-tumor immune responses and promote metastatic seeding. The high endothelial venules (HEVs) together with CCL21-expressing fibroblastic reticular cells (FRCs) are essential for lymphocyte recruitment into the LNs. We established multicolor antibody panels for evaluation of HEVs and FRCs in TDLNs from breast cancer (BC) patients. Our data show that patients with invasive BC display extensive structural and molecular remodeling of the HEVs, including vessel dilation, thinning of the endothelium and discontinuous expression of the HEV-marker PNAd. Remodeling of the HEVs was associated with dysregulation of CCL21 in perivascular FRCs and with accumulation of CCL21-saturated lymphocytes, which we link to loss of CCL21-binding heparan sulfate in FRCs. These changes were rare or absent in LNs from patients with non-invasive BC and cancer-free organ donors and were observed independent of nodal metastasis. Thus, pre-metastatic dysregulation of core stromal and vascular functions within TDLNs reflect the primary tumor invasiveness in BC. This adds to the understanding of cancer-induced perturbation of the immune response and opens for prospects of vascular and stromal changes in TDLNs as potential biomarkers.
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| 8. |
- Bekkhus, Tove, et al.
(författare)
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Stromal transdifferentiation drives lipomatosis and induces extensive vascular remodeling in the aging human lymph node
- 2023
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Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 259:3, s. 236-253
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Tidskriftsartikel (refereegranskat)abstract
- Lymph node (LN) lipomatosis is a common, but rarely discussed phenomenon, associated with aging, involving a gradual exchange of the LN parenchyma into adipose tissue. The mechanisms behind these changes and the effects on the LN are unknown. We show that LN lipomatosis starts in the medullary regions of the human LN and link the initiation of lipomatosis to transdifferentiation of LN fibroblasts into adipocytes. The latter is associated with a downregulation of lymphotoxin beta expression. We also show that, isolated medullary and CD34+ fibroblast, in contrast to the reticular cells of the T-cell zone, display an inherent higher sensitivity for adipogenesis. Progression of lipomatosis leads to a gradual loss of the medullary lymphatic network, but at later stages, collecting-like lymphatic vessels, are found inside the adipose tissue. The stromal dysregulation includes a dramatic remodeling and dilation of the high endothelial venules associated with reduced density of naïve T-cells. Abnormal clustering of plasma cells is also observed. Thus, LN lipomatosis causes widespread stromal dysfunction with consequences for the immune contexture of the human LN. Our data warrant an increased awareness of LN lipomatosis as a factor contributing to decreased immune functions in the elderly and in disease.
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| 9. |
- Bekkhus, Tove
(författare)
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The role of the lymph node stroma in cancer and aging
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The function of the lymph node (LN) stroma is crucial for the induction of an adaptive immune response. The stroma includes lymphatic vessels, high endothelial venules (HEVs) and mesenchymal cells (MCs). In this thesis, I have been investigating the role of the LN stroma in cancer and aging. In Paper I, we demonstrate that LNs draining invasive breast cancer present remodeling of the HEVs and dysregulation of the perivascular MCs. Dilation of HEVs is correlating with inhibition of normal lymphocyte recruitment due to perivascular changes in the expression of molecular cues necessary for chemotaxis. As a follow up of Paper I, we created an automatic method for image analysis of HEVs by using artificial intelligence and deep learning. In paper II, we validate the HEV-finder that we suggest is a good automatic image analysis tool to study HEV remodeling in different subtypes of cancer and to perform survival studies in larger patient cohorts. In paper III, we present a mapping of the lymphatic endothelial cells (LECs) of the mouse and human LNs by using single-cell RNA sequencing and present a new LEC subset called PTX3-LECs. We demonstrate that both in mouse and human LNs there are four LEC subsets, forming the subcapsular and medullary sinuses where immune cells enter and exit the LN, respectively. Our mapping is a great tool for further investigation of different subsets and their specific genes in translational studies of homeostasis or disease. In paper IV, we are focusing on LN lipomatosis, which is an age-related phenomenon where the normal LN parenchyma is replaced by adipose tissue. Our data support that LN lipomatosis is developing in the medulla of the LN due to transdifferentiation of medullary MCs into adipocytes. We found that it is causing remodeling of the HEVs and loss of medullary lymphatic vessels, affecting both the entry and exit of lymphocytes. Based on our findings, we suggest that LN lipomatosis is a contributing factor in immunodeficiency in elderly. In paper V, we created a new transplantable breast cancer model in mouse to study the effect of LN metastasis by inducing the expression of the chemokine receptor CCR7 in the mammary carcinoma cell line EO771. The new model will allow us to study the effect of LN metastasis on the anti-tumor immunity and response to therapy. In summary, my thesis shed light on the importance of a functioning LN stroma in both cancer and aging and provides new tools for image analysis, translational studies of the LN stroma and models for LN metastasis.
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| 10. |
- Hernández Vásquez, Magda, et al.
(författare)
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Transcription factor FOXP2 is a flow-induced regulator of collecting lymphatic vessels
- 2021
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Ingår i: EMBO Journal. - : EMBO Press. - 0261-4189 .- 1460-2075. ; 40:12
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Tidskriftsartikel (refereegranskat)abstract
- The lymphatic system is composed of a hierarchical network of fluid absorbing lymphatic capillaries and transporting collecting vessels. Despite distinct functions and morphologies, molecular mechanisms that regulate the identity of the different vessel types are poorly understood. Through transcriptional analysis of murine dermal lymphatic endothelial cells (LECs), we identified Foxp2, a member of the FOXP family of transcription factors implicated in speech development, as a collecting vessel signature gene. FOXP2 expression was induced after initiation of lymph flow in vivo and upon shear stress on primary LECs in vitro. Loss of FOXC2, the major flow-responsive transcriptional regulator of lymphatic valve formation, abolished FOXP2 induction in vitro and in vivo. Genetic deletion of Foxp2 in mice using the endothelial-specific Tie2-Cre or the tamoxifen-inducible LEC-specific Prox1-CreERT2 line resulted in enlarged collecting vessels and defective valves characterized by loss of NFATc1 activity. Our results identify FOXP2 as a new flow-induced transcriptional regulator of collecting lymphatic vessel morphogenesis and highlight the existence of unique transcription factor codes in the establishment of vessel-type-specific endothelial cell identities.
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