Tertiary Lymphoid Tissue in the Tumor Microenvironment: From Its Occurrence to Immunotherapeutic Implications

Abstract

Recruitment of immune and inflammatory cells in the microenvironment of solid tumors is highly heterogeneous and follows patterns, varying according to the organ of origin and stage of disease, with critical roles in the process of cancer onset and progression. While adaptive cells are endowed with anti-tumor activities, inflammatory components of the immune infiltrate orchestrate an immunosuppressive microenvironment that reveals ambivalent functions of the immune contexture in the tumor milieu. The balance between opposing pro-tumoral and anti-tumoral immune pathways, which occur concomitantly in the tumor microenvironment, and the regulatory networks of these phenomena have been the target of several immunotherapeutic strategies. While the scarcity of adaptive immune effectors in tumors correlates with dismal prognosis, the pathways of activation of tumor-specific lymphocytes are yet to be fully elucidated. Recently, the occurrence of tertiary lymphoid tissue was revealed to be critical in mediating the dynamics of T cell recruitment and local activation of immune cells in the tumor microenvironment. Thus, tertiary lymphoid tissue assessment and targeting emerge as a promising approach for the design of novel prognostic immune signatures and immunotherapeutic strategies. The immunological behavior of tertiary lymphoid tissue, its occurrence in the tumor immune microenvironment and its clinical relevance are discussed here.

Complex Immune Contextures Characterise Malignant Peritoneal Mesothelioma: Loss of Adaptive Immunological Signature in the More Aggressive Histological Types

“…The pattern of tumour-infiltrating lymphocyte (TIL) distribution identified dispersed lymphocytes or the presence of discrete lymphoid aggregates with features of ELSs mainly at the edges of large tumour nodules (Supplementary Figure S4A ). ELSs are lymphoid structures that develop in nonlymphoid tissue and have an organisation similar to that of lymph nodes [ 22 , 23 ]. In our samples, they showed discrete T (CD3 + ) and B (CD20 + ) cell areas, the first containing a CD21-positive follicular dendritic cell (FDC) network and the latter VEGFR2-positive endothelial venules, thus fulfilling the criteria for organised lymphoid structures (Supplementary Figure S4 ) [ 22 , 23 ].…”

NOVA1 inhibition by miR-146b-5p in the remnant tissue microenvironment defines occult residual disease after gastric cancer removal

“…Stromal spindle cells are major components of tissue inflammation or tertiary lymphoid structures within the microenvironment. [ 16 – 18 ] Recent studies showed that stromal spindle cells and fibroblasts actively regulate immune cells in the inflammatory process and are involved in immune escape of cancers. [ 16 , 34 , 35 ] In addition, fibroblasts and stromal spindle cells, or cancer-associated fibroblasts (CAFs), are major components of the tissue matrix.…”

Implications of NOVA1 suppression within the microenvironment of gastric cancer: association with immune cell dysregulation

“…The secondarily induced NOVA1 suppression in spindle cells and T cells may result in abnormal tissue matrix function and immune regulation. In fact, stromal spindle cells actively regulate immune cells, as they are major components of tissue inflammation or tertiary lymphoid structures within the microenvironment [1][2][3]. Therefore, blocked NOVA1 function in these microenvironment cells may be related to immune escape of aggressive cancers.…”

“…Tumor growth involves coevolutionary processes among tumor cells, extracellular matrix, vasculatures, and immune cells [1]. Cancer-associated inflammation or tertiary lymphoid structures made by ectopically accumulated immune lymphoid cells and matrix components are formed within the tumor microenvironment as an immune reaction in response to stimuli of tumor growth [1][2][3][4][5].…”

“…S1). Given that stromal spindle cells such as fibroblasts are major components of tissue inflammation or tertiary lymphoid structures within the microenvironment [1][2][3] and that these cells actively regulate immune cells in the inflammatory process [1], NOVA1 seems to be induced in ectopically accumulated T cells via active interaction with stromal spindle cells during the immune response or inflammatory processes [11]. However, in cancer-associated inflammation or tertiary lymphoid structures, NOVA1 expression is frequently suppressed in T cells within the gastric cancer microenvironment, and that suppression correlates with poor survival in advanced gastric cancer patients [11].…”