Fig. 1

TLS formation modelling. (a) The initial process of TLS. Local accumulation of pro-inflammatory molecules and chemokines can recruit lymphoid tissue-inducing (LTi) cells to sites of inflammation. LTi cells interact with local lymphoid tissue organizer (LTo) cells to initiate expression of various cytokines (IL-7, IL-17 and RANKL) and cytokine receptors (IL-7R, IL-17R and RANK) and TLS development. Many immune cells can replace LTi cells, such as T helper 17 (Th17) cells, CD8 + T cells, B cells, M1-polarized macrophages, innate lymphoid cell-3(ILC3) and natural killer cells. Similarly, cancer-associated fibroblast (CAF), vascular smooth muscle cells (VAMC) and adipocyte can replace LTo cells. Through the binding of lymphotoxin α1β2 (LTα1β2) to LTβ receptor (LTβR), this signaling pathway promotes the secretion of vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor C (VEGFC) to promote HEV development. It can also promote the secretion of adhesion molecules used to recruit immune cells, such as vascular adhesion molecule 1 (VCAM 1), intercellular adhesion molecule 1 (ICAM1), and mucosal vascular addressin cell adhesion molecule 1 (MADCAM 1) as well as chemokines (CCL19, CCL21, CXCL12, and CXCL13). These chemokines induce LTα1β2 expression on lymphocytes, recruit lymphocytes from nearby HEVs into TLS and form T-cell and B-cell zones. (b) The maturity stage of TLS. Maturation of TLS undergoes three stages of evolution. From loose lymphoid aggregates to primary follicles of T and B cells with macrophages and DCs, to mature polarized structures containing GCs, host cells, HEVs, and lymph vessels (LVs). (c) The location of TLS in the body. The location of TLS in the human body includes stromal, peritumoral and intratumoral. IL-7, interleukin-7; RANK, NF-κB receptor activator; RANKL, NF-κB ligand receptor activator; CCL19, C-C motif chemokine 19; CXCL12, C-X-C motif chemokine 12