Melanoma‐derived extracellular vesicles mediate lymphatic remodelling and impair tumour immunity in draining lymph nodes

Leary, Noelle; Walser, Sarina; He, Yuliang; Cousin, Nikola; Pereira, Paulo; Gallo, Alessandro; Collado-Díaz, Víctor; Halin, Cornelia; García‐Silva, Susana; Peinado, Héctor; Dieterich, Lothar C.

doi:10.1002/jev2.12197

Cited by 71 publications

(59 citation statements)

References 72 publications

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“…Tumor-draining inguinal LNs from mice bearing B16F10-luc2 melanomas ( N = 3) were harvested on day 14 for sorting of LECs by FACS and processed in parallel with our previous study for scRNA-seq [ 18 ]. ScRNA-seq data of the naive control is accessible at ArrayExpress under the accession number E-MTAB-10434.…”

Section: Methodsmentioning

confidence: 99%

“…Of note, these changes may occur before metastatic colonization of the LNs, indicating the involvement of tumor-derived factors, such as extracellular vesicles (EVs) and soluble growth factors carried by afferent lymph [ 12 , 13 , 14 , 15 ]. Melanoma-derived EVs have been shown to interact directly with LN-resident LECs [ 16 , 17 , 18 ], inducing lymphangiogenesis and subsequent metastasis [ 17 , 18 ]. LN LECs have also been implicated in tumor immune evasion and immunotherapy resistance by cross-presenting tumor-derived antigens [ 19 ] and by expressing the T cell-inhibitory molecule PD-L1 [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

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

Sibler

Ducoli

et al. 2022

Cancers

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sibler

Ducoli

et al. 2022

Cancers

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“…For example, tumor-draining LNs undergo massive remodeling, including accumulation of immunosuppressive cells, reprogramming of stromal cells and vascular remodeling [ 153 – 155 ]. Leary et al found that extracellular vesicles derived from melanoma cells selectively interact with LN resident macrophages and lymphatic endothelial cells, induce LN remodeling and eventually impair anti-tumor immunity [ 156 ]. Therefore, how to adapt to the changing lymphatic microenvironment should be considered in vaccine development.…”

Section: Challenges Of Self-adjuvanting Nanovaccines For Cancer Therapymentioning

confidence: 99%

Self-adjuvanting cancer nanovaccines

Liao

Huang

et al. 2022

J Nanobiotechnol

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Nanovaccines, a new generation of vaccines that use nanoparticles as carriers and/or adjuvants, have been widely used in the prevention and treatment of various diseases, including cancer. Nanovaccines have sparked considerable interest in cancer therapy due to a variety of advantages, including improved access to lymph nodes (LN), optimal packing and presentation of antigens, and induction of a persistent anti-tumor immune response. As a delivery system for cancer vaccines, various types of nanoparticles have been designed to facilitate the delivery of antigens and adjuvants to lymphoid organs and antigen-presenting cells (APCs). Particularly, some types of nanoparticles are able to confer an immune-enhancing capability and can themselves be utilized for adjuvant-like effect for vaccines, suggesting a direction for a better use of nanomaterials and the optimization of cancer vaccines. However, this role of nanoparticles in vaccines has not been well studied. To further elucidate the role of self-adjuvanting nanovaccines in cancer therapy, we review the mechanisms of antitumor vaccine adjuvants with respect to nanovaccines with self-adjuvanting properties, including enhancing cross-presentation, targeting signaling pathways, biomimicking of the natural invasion process of pathogens, and further unknown mechanisms. We surveyed self-adjuvanting cancer nanovaccines in clinical research and discussed their advantages and challenges. In this review, we classified self-adjuvanting cancer nanovaccines according to the underlying immunomodulatory mechanism, which may provide mechanistic insights into the design of nanovaccines in the future. Graphical Abstract

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“…They showed that sEVs are transported and taken up by LECs in a VCAM-1 dependent fashion, which led to gene expression changes and proliferation in these cells. Additionally, sEVs impaired tumor immunity by shuttling MHC-1 to LECs [95].…”

Section: Lymphangiogenesismentioning

confidence: 99%

The Role of Extracellular Vesicles in Melanoma Progression

Lattmann

Levesque

2022

Cancers

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Cutaneous melanoma arises from a malignant transformation of the melanocytes in the skin. It is the deadliest form of skin cancer owing to its potential to metastasize. While recent advances in immuno-oncology have been successful in melanoma treatment, not all the patients respond to the treatment equally, thus individual pre-screening and personalized combination therapies are essential to stratify and monitor patients. Extracellular vesicles (EVs) have emerged as promising biomarker candidates to tackle these challenges. EVs are ~50–1000-nm-sized, lipid bilayer-enclosed spheres, which are secreted by almost all cell types, including cancer cells. Their cargo, such as nucleic acids, proteins, lipids, amino acids, and metabolites, can be transferred to target cells. Thanks to these properties, EVs can both provide a multiplexed molecular fingerprint of the cell of origin and thus serve as potential biomarkers, or reveal pathways important for cancer progression that can be targeted pharmaceutically. In this review we give a general overview of EVs and focus on their impact on melanoma progression. In particular, we shed light on the role of EVs in shaping the tumor–stroma interactions that facilitate metastasis and summarize the latest findings on molecular profiling of EV-derived miRNAs and proteins that can serve as potential biomarkers for melanoma progression.

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Melanoma‐derived extracellular vesicles mediate lymphatic remodelling and impair tumour immunity in draining lymph nodes

Cited by 71 publications

References 72 publications

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

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

Self-adjuvanting cancer nanovaccines

The Role of Extracellular Vesicles in Melanoma Progression

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