Tertiary lymphoid structures as a biomarker in immunotherapy and beyond: Advancing towards clinical application

Tertiary lymphoid structures (TLSs) are ectopic immune cell clusters formed in nonlymphoid tissues affected by persistent inflammation, such as in cancer and prolonged infections. They have features of the structure and function of secondary lymphoid organs, featuring central CD20⁺ B cells, surrounded by CD3⁺ T cells, CD21⁺ follicular dendritic cells, and CD68⁺ macrophages, with a complex vascular system. TLS formation is governed by lymphotoxin-α1β2, TNF, and chemokines like CCL19, CCL21, and CXCL13, differing from secondary lymphoid organ development in developing later in life at sites of chronic inflammation. Their role in enhancing immune responses, particularly in the context of cancer, makes them a focal point in immunotherapy. This review discusses recent advances in TLS assessment that involves complex gene expression signatures, histological analysis, artificial intelligence, and spatial omics. The presence and maturity of TLS are associated with better outcomes in various cancers, acting as a biomarker for immunotherapy effectiveness. This review explores the structure, formation, and role of TLS in disease prognosis, including their roles in immunotherapy and non-immunotherapy treatments, highlighting a need to develop novel techniques for precise characterization of TLS as well as their significance as predictive biomarkers beyond traditional biomarkers.