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.

Keywords: gastrointestinal tumors; immune microenvironment; prediction; tertiary lymphoid structure; therapeutic targets.

Figure 1

The process of tumor-related TLSs formation and maturation. The process of tumor-related TLS formation and maturation have similarities with that of SLOs. When the tumor-associated antigens exposed to the TME caused an anti-tumor immune response, adaptive immune cells were activated, and then secreted lymphotoxin-α (LT-α) enabled them to interact with the corresponding receptor (lymphotoxin-β receptor, LT-βR) expressed on stromal cells (i.e., endothelial cells, fibroblasts, epithelial cells, monocytes, and dendritic cells). The secretion of CXCL13 and IL-7 can recruit the LTi to the lesion sites. The surface of the LTi expressed LT-α1β2, which can bind to LT-βR. After the binding, it promotes stromal cells to secrete vascular endothelial growth factor C (VEGFC)-induced HEV formation. It can also facilitate the secretion of adhesion molecules used to recruit immune cells, such as the vascular cell adhesion molecule 1 (VCAM1) and the intercell adhesion molecule 1 (ICAM1). CCL21 and CCL19 induce LTα1β2 expression in T cells, CXCL13 stimulates LTα1β2 expression in B cells, and it can recruit lymphocytes into TLS via the LTβR signaling-dependent pathway from nearby HEVs. Besides, the cytokine IL-36γ secreted by macrophages and endothelial cells contributes to TLS formation and maturation in gastrointestinal tumors.

Figure 2

The maturity classification of tertiary lymphoid structures. Representative images of tertiary lymphoid structures (TLSs) detected in formalin-fixed paraffin-embedded tumor sections by haematoxylin and eosin (H&E) staining. (A) Aggregation (AGG) (The region of red dotted line); (B) Primary follicles (FL-I) (The region of red dotted line); (C) Secondary follicles (FL-II) (The region of red dotted line with a germinal center) (The region of the yellow dotted line represents the germinal center). These histological images are original, unpublished images from the authors’ examination of tumors with gastric neuroendocrine neoplasms.