Jagged-1+ Tregs Mediate Lymphatic Remodeling in Tumour-Draining Lymph Nodes

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Jagged-1+ Tregs Mediate Lymphatic Remodeling in Tumour-Draining Lymph Nodes

Authors

Xu, J. Z.; Lui, P. P.; Tsai, P.-H.; Aziz, H.; Xie, B.; Cho, I.; Terranova-Barberio, M.; Li, C. Z.; Stoker, K.; Yu, H.; Denton, A. E.; Lawrence, T.; Karagiannis, S. N.; Ali, N.

Abstract

The tumour-draining lymph nodes (tdLNs) are crucial sites for early immune surveillance of tumours. During tumour development, tdLNs undergo significant stromal remodelling that impacts lymph node (LN) architecture. The reconstruction of tdLNs is dependent on the crosstalk between regulatory T cells (Tregs) and resident stromal cells. The Notch ligand Jagged1 (Jag1), highly expressed in skin Tregs, is critical for facilitating stem cell-mediated tissue regeneration. However, the role of Jag1pos Tregs in mediating the activity of tdLN-resident immune cells and stromal cells remains unexplored. Here, we used the B16-F10 tumour model to assess the role of Jag1pos Tregs during tdLN development. During tumor progression, late-stage tdLN Tregs expressed higher levels of Jag1 than early-stage tdLNs. Conditional deletion of Jag1 in Tregs markedly restrained tdLN expansion, without influencing effector T cell abundance or activation profile. Transcriptomic analysis of tdLNs revealed downregulation of lymphatic endothelial cell (LEC)-related markers in mice with Treg-specific Jag1 ablation. Disruption of lymphatic networks in the tdLN was further confirmed by flow cytometric profiling and histological analysis. In vivo permeability assessment by FITC-dextran demonstrated perturbed lymphatic drainage, likely due to suppressed LN lymphangiogenesis. Finally, we identify the presence of Jag1pos Tregs in tdLNs of human melanoma patients. Overall, our results highlight that crosstalk between Jag1pos Tregs and LECs is required for lymphatic sinus expansion, which is critical for the formation of the tdLN niche during melanoma progression.

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