Tertiary Lymphoid Structures: A Potential Biomarker for Anti-Cancer Therapy

Abstract

A tertiary lymphoid structure (TLS) is a special component in the immune microenvironment that is mainly composed of tumor-infiltrating lymphocytes (TILs), including T cells, B cells, DC cells, and high endothelial venules (HEVs). For cancer patients, evaluation of the immune microenvironment has a predictive effect on tumor biological behavior, treatment methods, and prognosis. As a result, TLSs have begun to attract the attention of researchers as a new potential biomarker. However, the composition and mechanisms of TLSs are still unclear, and clinical detection methods are still being explored. Although some meaningful results have been obtained in clinical trials, there is still a long way to go before such methods can be applied in clinical practice. However, we believe that with the continuous progress of basic research and clinical trials, TLS detection and related treatment can benefit more and more patients. In this review, we generalize the definition and composition of TLSs, summarize clinical trials involving TLSs according to treatment methods, and describe possible methods of inducing TLS formation.

Cell of origin alters myeloid-mediated immunosuppression in lung adenocarcinoma

“…Further investigating this difference in myeloid populations, we utilized a previously published spatial transcriptomic (ST-seq) dataset on an independent cohort of Sftpc + KRAS G12D LUAD, Gramd2 + KRAS G12D LUAD 13 , and controls to determine the frequency of macrophage-rich tertiary lymphoid structure (TLS), which emerge in non-lymphoid tissues under chronic inflammatory conditions, such as cancer 48 and play a crucial role in immune surveillance by facilitating the local activation of immune responses against tumor cells 49 with associated responsiveness to immunotherapies, such as immune checkpoint inhibitors [50][51][52][53] . TLS were calculated using a composite score expression for multiple immune cell types, including B cells: Igha, Ighg1, Ighg3, Ighm, Igkc, Iglc1, Iglc2, Iglc3, Jchain, Cd79a, Fcrl5, Mzb1, Ssr4, Xbp1; T cells: Trbc2, Il7r; for fibroblasts and stroma: Cxcl12, Lum; and for macrophages: C1qa, C7, Cd52, Apoe, Pim2, Derl3, Timd4, Cd163, and Folr2.…”

CXC ligand 13 orchestrates an immunoactive microenvironment and enhances immunotherapy response in head and neck squamous cell carcinoma

“… 27 In tumor environment, TLSs can promote immune cells to immerse into solid tumors, so the development of TLSs is significantly related to the survival rate of untreated patients. 28 , 29 Similarly, the development of TLSs is usually associated with improved treatment response in patients treated with immune checkpoint inhibitors. 29 , 30 This suggests that TLSs is the conjecture of producing anti-tumor immune sites.…”

“… 28 , 29 Similarly, the development of TLSs is usually associated with improved treatment response in patients treated with immune checkpoint inhibitors. 29 , 30 This suggests that TLSs is the conjecture of producing anti-tumor immune sites. IHC-based TLSs section analysis does have some limitations, though, including the need for excessive clinical sample consumption, inconvenience with quantitative analysis, complexity with combination analysis with TME, and difficulty with elucidating underlying mechanisms.…”

Tertiary lymphoid structures in pancreatic cancer: a new target for immunotherapy

“…DCs promote lymphocyte infiltration and production of TLSs, inhibit tumor growth, and play an antigen-presenting role in TLSs. In tumors with poor DC infiltration, TIL cell density is significantly reduced, with poor prognosis ( 80 ).…”