The Emerging Role of Tertiary Lymphoid Structures in Breast Cancer: A Narrative Review

Abstract

This narrative review aims to clarify the role of tertiary lymphoid structures in breast cancer. We examine their development, composition, and prognostic value, and current ways of recognizing them. A comprehensive literature review was performed using the PubMed/Medline, Scopus, and EMBASE databases. A significant area of interest in breast cancer research involves targeting immune checkpoint molecules, particularly in the triple-negative subtype, where treatment options remain limited. However, existing biomarkers have limitations in accurately predicting treatment response. In this context, tertiary lymphoid structures (TLSs) emerge as a prognostic biomarker and also as a promising predictive marker for response. TLSs are ectopic lymphoid formations or neo-organogenesis that can develop after prolonged exposure to inflammatory signals mediated by chemokines and cytokines. Their presence is inversely correlated with estrogen receptor (ER) and/or progesterone receptor (PR) expression, but positively associated with a higher pathologic complete response rate and improved overall survival. In certain scenarios, TLS-positive tumors were associated with improved outcomes regardless of the presence of PDL-1 (programmed cell death ligand 1) expression or TILs (tumor-infiltrating lymphocytes).

Keywords: biomarkers; breast cancer; immunotherapy; lymphocytes; prognostic factors; tertiary lymphoid structures.

Figure 1

The composition of a tertiary lymphoid structure includes B cells which are mostly intermingled, but occasionally they form distinct B cell and T cell compartments resembling those found in lymph nodes. TLSs lack a capsule and exhibit high endothelial venules (HEVs) in their architecture. The T cell zone contains mature dendritic cells and fibroblastic reticular cells, whereas the B cell zone has a germinal center with plasma cells, macrophages, and follicular dendritic cells.