Tertiary lymphoid structures (TLS) are clusters of immune cells that form outside of typical lymph nodes and the spleen, often in sites of chronic inflammation. These structures have gained significant attention in cancer research due to their role in influencing the body’s immune response against tumors. Their presence within or near tumors represents a new frontier in understanding and potentially improving cancer treatments.
Understanding Tertiary Lymphoid Structures
Tertiary lymphoid structures (TLS) are organized aggregates of immune cells that resemble conventional lymph nodes, though they lack a distinct capsule. They are often found in non-lymphoid tissues, including chronically inflamed areas and within the tumor microenvironment (TME). TLS primarily consist of T cells, B cells, and dendritic cells (DCs). Other cells like follicular dendritic cells (FDCs), fibroblastic reticular cells (FRCs), macrophages, and endothelial cells also contribute.
These structures are characterized by distinct zones, with T cell-rich areas often surrounding a central B cell-rich zone. FDCs, found predominantly in B cell zones, present antigens and support B cell differentiation. High endothelial venules (HEVs), specialized blood vessels, are also present within TLS and facilitate immune cell recruitment from the bloodstream. TLS formation is a response to inflammatory stimuli, involving immune cell recruitment and the compartmentalization of T and B cells.
How TLS Influence Cancer Immunity
Tertiary lymphoid structures function as localized “mini-immune organs” within the tumor microenvironment, orchestrating immune responses directly at the site of disease. These structures facilitate the recruitment, activation, and maturation of various immune cells, including T cells and B cells, which can then recognize and attack cancer cells. Within TLS, follicular dendritic cells (FDCs) present antigens to B cells, supporting their differentiation into antibody-producing plasma cells and contributing to humoral immunity.
The presence of TLS can lead to a more “inflamed” or “hot” tumor environment, which is generally associated with a more effective anti-tumor immune response. This “hot” tumor characteristic is due to the aggregation of T and B lymphocytes along with antigen-presenting cells and high endothelial venules, mimicking the organization seen in secondary lymphoid tissues. Active B cells within mature TLS not only contribute to potent humoral immunity but also augment T cell-mediated immune responses, both important for controlling tumor growth. The presence of active immune cells and their secreted proteins within TLS contributes to anti-tumor activity, though their precise formation and functional pathways are still being elucidated.
TLS and Responses to Cancer Therapies
The presence and characteristics of tertiary lymphoid structures (TLS) correlate with the effectiveness of various cancer treatments, particularly immunotherapies. Well-formed TLS can act as a biomarker, indicating a more favorable prognosis and a higher likelihood of responding to specific drugs like immune checkpoint inhibitors (ICIs). For example, patients with TLS-positive tumors often experience improved survival and better responses to anti-PD-1/PD-L1 and anti-CTLA-4 immunotherapies.
This correlation has been noted across multiple cancer types, including metastatic melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma, and soft tissue sarcoma. In NSCLC, a heightened signaling of plasma cells within TLS was linked to increased overall survival following anti-PD-L1 therapy. Similarly, the co-occurrence of tumor-associated CD8+ T cells and CD20+ B cells, often found within TLS, has shown a significant association with improved survival in metastatic melanoma patients receiving immune checkpoint inhibition. The density, location, and maturity of TLS can influence their prognostic value, but mature TLS with a well-defined structure and robust immune function are associated with better anti-tumor immune responses.
Harnessing TLS for Cancer Treatment
Research is actively exploring therapeutic strategies to manipulate or induce the formation of tertiary lymphoid structures (TLS) within tumors to enhance anti-tumor immunity and improve treatment outcomes. One promising approach involves oncolytic viruses, engineered to selectively infect, replicate in, and destroy cancer cells while stimulating an immune response. These viruses can act as immunoadjuvants, promoting TLS formation within the tumor microenvironment and potentially amplifying anti-tumor immune responses, especially when combined with immunotherapies like immune checkpoint blockade.
Another strategy focuses on administering specific cytokines and chemokines that drive TLS development. For example, factors like lymphotoxins (LIGHT/LTα/LTβ) and TNFα, along with certain CC/CXC chemokines, are involved in TLS formation. Promoting the expression or delivery of these molecules in preclinical models has shown potential in inducing TLS, suggesting avenues for future clinical interventions. While the precise mechanisms for inducing TLS are still under investigation, these efforts aim to transform “cold” (non-inflamed) tumors into “hot” (inflamed) ones, making them more responsive to existing and new cancer therapies.