Turning Tertiary Lymphoid Structures (TLS) into Hot Spots: Values of TLS in Gastrointestinal Tumors

Abstract

Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregation structures found in the tumor microenvironment (TME). Emerging evidence shows that TLSs are significantly correlated with the progression of gastrointestinal tumors, patients’ prognosis, and the efficacy of adjuvant therapy. Besides, there are still some immunosuppressive factors in the TLSs that may affect the anti-tumor responses of TLSs, including negative regulators of anti-tumor immune responses, the immune checkpoint molecules, and inappropriate tumor metabolism. Therefore, a more comprehensive understanding of TLSs’ responses in gastrointestinal tumors is essential to fully understand how TLSs can fully exert their anti-tumor responses. In addition, targeting TLSs with immune checkpoint inhibitors and vaccines to establish mature TLSs is currently being developed to reprogram the TME, further benefiting cancer immunotherapies. This review summarizes recent findings on the formation of TLSs, the mechanisms of their anti-tumor immune responses, and the association between therapeutic strategies and TLSs, providing a novel perspective on tumor-associated TLSs in gastrointestinal tumors.

Association of systemic inflammatory markers and tertiary lymphoid structure with pathological complete response in gastric cancer patients receiving preoperative treatment: a retrospective cohort study

“…TLS were identified based on their morphology on H&E staining slides. Only mature TLS (maturation classification ii and iii 23 ) were evaluated in this study. TLS were categorized into two group according to their location: those in the tumor bed and those in adjacent normal tissue.…”

Chimeric Antigen Receptor T Cell Therapy for Hepatocellular Carcinoma: Where Do We Stand?

“…TLSs are specialized, ectopic lymphoid-like formations that emerge at sites of prolonged inflammation or chronic immune activation, distinct from conventional lymphoid organs like lymph nodes or the spleen. These structures share the features of secondary lymphoid organs and develop in non-lymphoid tissues in response to persistent antigenic stimulation, often seen in chronic infections, autoimmune disorders, transplanted organs, or cancer [ 57 , 58 , 59 , 60 , 61 , 62 ]. Recent findings underscore the significance of TLSs in orchestrating immune responses against tumors [ 63 ].…”

“…These zones typically comprise areas enriched in T cells, B cells, dendritic cells (DCs), follicular dendritic cells (FDCs), and high endothelial venules (HEVs) [ 64 ]. TLSs can influence local immune responses by promoting the recruitment and activation of immune cells, contributing to surveillance against tumor cells, shaping the dynamics of the tumor microenvironment and impacting overall anti-tumor immunity [ 62 , 65 ]. TLSs can be found in several solid tumors including HCC [ 66 ].…”

Epigenetic targets to enhance antitumor immune response through the induction of tertiary lymphoid structures

“…TFs such as Tcf7, Nfil3, and Tox function by stimulating epigenetic reprogramming, and they are critical for forming the three ILCs and LTi from early innate lymphoid precursors (EILP) ( 26 , 130 ). ILC3 and Th17 share the expression of retinoic acid-related orphan receptor γt (RORγt) with LTi and can act as surrogates for LTi ( 14 ). Other immune cells, such as Natural Killer (NK), B-cells, CD8 + T-cells, and macrophages, can also be potential surrogates for LTi ( 31 , 137 , 138 ).…”

“…TLS are ectopic aggregates of organized immune cells formed at sites of chronic inflammation and are seen in cancer, chronic infections, and autoimmune diseases ( 14 , 15 ). TLS share functional and structural similarities with secondary lymphoid organs (SLOs).…”