FIGURE 2.

Formation and maturation of tertiary lymphoid structures (TLSs) within the tumor microenvironment. (I) Depiction of the tumor microenvironment and its interactions with both innate and adaptive immune cells, and the non-immune components. (II) LTis attracted by the CXCL13 gradient, produced by activated stromal cells, migrate to the site of TLS initiation. Chemokines, such as CCL19, CCL21, CXCL12, and CXCL13, allow the migration and retention of additional LTis along with lymphocytes. The gathering of leukocytes surrounded by an extracellular matrix net produced by fibroblasts and newly formed blood vessels supports immature TLS formation, which fails to mount effective anti-tumor responses. (III) The presence of clearly delimited T cell and B cell zones, as well as a GC-like structure, defines mature TLSs. In this structure, the induction of plasma cells and memory B cells takes place, reflecting the interaction with other specific cell types, such as FDCs, T_FH, and CD8⁺ T cells. Surrounded by pericytes and expressing adhesion molecules, the normal high endothelial venules (HEVs) located at the TLS vicinity favor the formation of mature TLSs, which are thought to be a rich niche of anti-tumor B and T cell responses.