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

Abstract

Tertiary lymphoid structures (TLS) are ectopic lymphoid organs that have been observed in chronic inflammatory conditions including cancer, where they are thought to exert a positive effect on prognosis. Both immune and non-immune cells participate in the genesis of TLS by establishing complex cross-talks requiring both soluble factors and cell-to-cell contact. Several immune cell types, including T follicular helper cells (Tfh), regulatory T cells (Tregs), and myeloid cells, may accumulate in TLS, possibly promoting or inhibiting their development. In this manuscript, we propose to review the available evidence regarding specific aspects of the TLS formation in solid cancers, including 1) the role of stromal cell composition and architecture in the recruitment of specific immune subpopulations and the formation of immune cell aggregates; 2) the contribution of the myeloid compartment (macrophages and neutrophils) to the development of antibody responses and the TLS formation; 3) the immunological and metabolic mechanisms dictating recruitment, expansion and plasticity of Tregs into T follicular regulatory cells, which are potentially sensitive to immunotherapeutic strategies directed to costimulatory receptors or checkpoint molecules.

Localization and density of tertiary lymphoid structures associate with molecular subtype and clinical outcome in colorectal cancer liver metastases

“… 39 40 In addition, Tfh and Treg cells have been reported to act in a complex balance in TLS formation and influence the composition of the neoplastic chronic inflammatory microenvironment. 41 Another study demonstrated that antigen-induced IL-2 production promoted the accumulation of Treg cells, and then contributed to the suppression of Th1-mediated adaptive immune responses. Subsequently, the IL-2-depleted microenvironment transformed some activated CD4 + T cells into Tfh cells, which promoted the formation of TLSs and recruitment of tumor-infiltrating B cells.…”

Epigenetic targets to enhance antitumor immune response through the induction of tertiary lymphoid structures

“…Studies in preclinical mouse models show that the interactions between stromal cells and hematopoietic lymphoid tissue-inducer cells (LTi) initiate TLS and SLO development ( 22 , 23 ) ( Figure 1 ). TLS development starts when APCs deliver tumor-associated antigens to adaptive immune cells, resulting in lymphocyte activation and cytokine secretion [e.g., Interleukin-7(IL-7)] ( 24 ).…”

Systems immunology spanning tumors, lymph nodes, and periphery

“…The tumor stroma and lymphatic vessels have been found to undergo extensive remodeling and expansion within the tumor microenvironment. 7 , 49 Non-immune cells associated with the tumor stroma, such as cancer-associated fibroblasts (CAFs), also play many crucial roles in cancer progression, including the exclusion of T cells from the tumor core via extracellular matrix (ECM) remodeling or expression of immunosuppressive molecules. 173 Overexpression of key vascular endothelial growth factors by CAFs and tumor cells promotes the formation of new vessels and enlargement of lymphatic vessels, which enhances tumor growth and dissemination.…”

“… 6 Immune structures organized to varying degrees, including tertiary lymphoid aggregates (TLAs), mature tertiary lymphoid structures (mTLSs) or ectopic lymphoid structures (ELSs), and immune infiltrates of myeloid origin, can be found modulating the tumor microenvironment across solid tumors. 7 , 8 The location and density of these structures have been proven to have prognostic value, and it is hypothesized that they might contain potential for immunotherapeutic targeting. 9 These immune structures can evolve over time and self-organize into highly ordered structures that resemble lymph nodes, particularly with T cell-rich zones and germinal centers that disseminate humoral immunity.…”