Inducible Tertiary Lymphoid Structures: Promise and Challenges for Translating a New Class of Immunotherapy

Abstract

Tertiary lymphoid structures (TLS) are ectopically formed aggregates of organized lymphocytes and antigen-presenting cells that occur in solid tissues as part of a chronic inflammation response. Sharing structural and functional characteristics with conventional secondary lymphoid organs (SLO) including discrete T cell zones, B cell zones, marginal zones with antigen presenting cells, reticular stromal networks, and high endothelial venues (HEV), TLS are prominent centers of antigen presentation and adaptive immune activation within the periphery. TLS share many signaling axes and leukocyte recruitment schemes with SLO regarding their formation and function. In cancer, their presence confers positive prognostic value across a wide spectrum of indications, spurring interest in their artificial induction as either a new form of immunotherapy, or as a means to augment other cell or immunotherapies. Here, we review approaches for inducible (iTLS) that utilize chemokines, inflammatory factors, or cellular analogues vital to TLS formation and that often mirror conventional SLO organogenesis. This review also addresses biomaterials that have been or might be suitable for iTLS, and discusses remaining challenges facing iTLS manufacturing approaches for clinical translation.

Tertiary Lymphatic Structures in Primary Hepatic Carcinoma: Controversy Cannot Overshadow Hope

“…LTIs further produce IL-17, lymphotoxin α-1β-2 (LTα1β2) and bind to lymphotoxin β receptor (LTβR) expressed on lymphoid tissues to form organizers. They further continue to induce the secretion of chemokines, expression of angiogenic growth factor, and expression of adhesion factors IL-17R + stromal cells ( 33 ). Cell inflammatory factors and lymphoid chemokines (such as CXCL-13, CCL-21, CCL-19, and CXCL-12) secreted by LTIs can coordinate early recruitment of T cells and B cells and form simple aggregates ( 34 ).…”

Surgical Considerations for Tumor Tissue Procurement to Obtain Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

“…During prosection, zones within the resected lesion should be selected that are more likely to be highly infiltrated with TILs; preferred sites include areas at the periphery of the tumor mass and areas adjacent to blood or lymphatic vessels, as these may be more likely to contain tertiary lymphoid structures formed from lymphocytes and antigen-presenting cells within the tumor in response to chronic inflammation. 44 The tumor must be carefully prosected by the operating surgeon in sterile fashion, with care to exclude nontumor tissue. Necrotic, hypervascular, or adipose tissue remaining in the resected tumor tissue correlates negatively with TIL growth ex vivo.…”

Stromal and Immune Cell Dynamics in Tumor Associated Tertiary Lymphoid Structures and Anti-Tumor Immune Responses

“…pathological loci, under stress conditions and as the result of persistent antigen stimulation (Sautes- . TLS structure resembles that of conventional secondary lymphoid organs (for example, lymph nodes) including B cell zones, T cell zones, marginal zones with activated macrophages and dendritic cells, reticular fibroblast cell networks and vasculature permissive to immune cell extravasation (Aoyama et al, 2021). However, while lymph nodes are encapsulated, TLS represent a congregation of immune and stromal cells confined within an organ or tissue (Aoyama et al, 2021).…”

“…TLS structure resembles that of conventional secondary lymphoid organs (for example, lymph nodes) including B cell zones, T cell zones, marginal zones with activated macrophages and dendritic cells, reticular fibroblast cell networks and vasculature permissive to immune cell extravasation (Aoyama et al, 2021). However, while lymph nodes are encapsulated, TLS represent a congregation of immune and stromal cells confined within an organ or tissue (Aoyama et al, 2021). TLS form de novo in the microenvironment of solid tissues in response to prolonged inflammatory stimuli including cancer and may dissipate upon the resolution of inflammation (Moyron-Quiroz et al, 2004).…”