The Role of Interleukin-7 in the Formation of Tertiary Lymphoid Structures and Their Prognostic Value in Gastrointestinal Cancers

Abstract

Immunotherapies for the treatment of solid tumors continue to develop in preclinical and clinical research settings. Unfortunately, for many patients the tumor fails to respond or becomes resistant to therapies such as checkpoint inhibitors (CPIs) targeting programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4). In many cancers, failed response to CPIs can be attributed to poor T cell infiltration, dominant immunosuppression, and exhausted immune responses. In gastrointestinal (GI) cancers T cell infiltration can be dismal, with several reports finding that CD8+ T cells compose less than 2% of all cells within the tumor. Organized aggregates of lymphocytes, antigen-presenting cells, and vessels, together termed tertiary lymphoid structures (TLSs), are hypothesized to be a major source of T cells within solid tumors. The intratumoral formation of these organized immune centers appears to rely on intricate cytokine and chemokine signaling to heterogeneous cell populations such as B and T cells, innate lymphoid cells, fibroblasts, and dendritic cells. In GI cancers, the presence and density of TLSs provide prognostic value for predicting outcome and survival. Further, TLS presence and density associates with favorable responses to CPIs in many cancers. This review highlights the prognostic value of TLSs in GI cancers, the role of the homeostatic cytokine interleukin-7 (IL-7) in TLS formation, and the induction of TLSs in solid tumors by novel therapeutics.

Identifying specific TLS-associated genes as potential biomarkers for predicting prognosis and evaluating the efficacy of immunotherapy in soft tissue sarcoma

“…Further studies are required to determine the specific mechanisms. TLSs have been reported to be associated with increased infiltration of B and T cells ( 32 ). We found that the TLS hub gene, TNFSF14, was enriched in a T-cell cluster based on single-cell sequencing analysis.…”

Tertiary lymphoid structural heterogeneity determines tumour immunity and prospects for clinical application

“…The formation of TLS depends on intricate ligand-receptor interactions between different cell types, including innate lymphocytes (ILCs), stromal cells, endothelial cells and B cells. CD3-CD4-/+ CXCR5IL-7Rα + hi ILCs, also known as lymphoid tissue inducing cells (LTi), are an essential component of SLO development [22]. Stromal fibroblasts, characterized by the expression of podoplanin and fibroblast activation protein-α (FAP), have been shown to be associated with the formation of TLS in both mouse and human models [23,24].…”