Tertiary Lymphoid Structures: Pivotal Players in Cancer Prognosis and Therapeutic Response

Introduction

Tertiary lymphoid structures (TLSs) are ectopic, organized lymphoid aggregates that develop in non-lymphoid tissues under conditions of chronic inflammation, including cancer, autoimmune diseases, and chronic infections. Unlike secondary lymphoid organs (SLOs) such as lymph nodes and spleen, TLSs arise in peripheral tissues where they facilitate localized immune responses. In cancer, TLSs have emerged as critical determinants of patient prognosis and response to immunotherapy. Their presence correlates with improved survival in multiple malignancies, suggesting a key role in antitumor immunity. This review explores the biology of TLSs, their formation, functional significance in cancer, and their potential as biomarkers and therapeutic targets.

Structure and Composition of Tertiary Lymphoid Structures

TLSs resemble secondary lymphoid organs in their organization, often containing distinct T-cell zones, B-cell follicles, germinal centers, and high endothelial venules (HEVs). They may also include dendritic cells, follicular helper T cells (Tfh), and plasma cells, depending on their maturation stage. Mature TLSs exhibit well-defined germinal centers, indicating active immune cell interactions, while immature TLSs lack such organization but still contribute to immune surveillance. The presence of HEVs facilitates lymphocyte recruitment, enhancing immune cell infiltration into tumors.

Mechanisms of TLS Formation in Cancer

The development of TLSs is driven by chronic inflammation and lymphoid chemokines such as CXCL13, CCL19, and CCL21, which recruit lymphocytes and organize their spatial distribution. Tumor-associated factors, including cytokines, stromal cell interactions, and neoantigen exposure, further promote TLS formation. Key transcription factors like lymphotoxin-α (LTα) and nuclear factor-κB (NF-κB) play crucial roles in their induction. Interestingly, certain cancers, such as melanoma, lung adenocarcinoma, and colorectal cancer, exhibit higher TLS prevalence, correlating with better clinical outcomes.

TLSs as Prognostic Biomarkers in Cancer

Multiple studies have demonstrated that TLSs are associated with favorable prognosis across various cancers. In non-small cell lung cancer (NSCLC), their presence correlates with prolonged survival and reduced recurrence. Similarly, in breast cancer, TLSs are linked to improved responses to chemotherapy and immunotherapy. The density and maturity of TLSs further refine their prognostic value, with mature TLSs exhibiting stronger associations with positive outcomes. These findings suggest that TLS assessment could enhance risk stratification and guide treatment decisions.

TLSs and Response to Immunotherapy

The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, yet response rates remain variable. Emerging evidence indicates that TLSs enhance immunotherapy efficacy by fostering pre-existing antitumor immunity. Tumors with TLSs often exhibit higher T-cell infiltration and a more favorable immune microenvironment, making them more responsive to PD-1/PD-L1 blockade. Additionally, TLS-derived plasma cells produce antitumor antibodies, further amplifying immune-mediated tumor destruction. Strategies to induce TLS formation, such as oncolytic viruses or cytokine-based therapies, are being explored to sensitize "cold" tumors to immunotherapy.

Therapeutic Strategies Targeting TLSs

Given their prognostic and predictive value, TLSs represent a promising therapeutic target. Approaches to enhance TLS formation include:

• Cytokine-based therapies (e.g., recombinant CXCL13, LTα) to promote lymphoid neogenesis.

• Vaccination strategies that boost intratumoral lymphoid aggregation.

• Combination therapies with ICIs to sustain TLS-mediated immune activation.
  Conversely, in autoimmune diseases, TLS inhibition may be desirable, highlighting the need for context-specific modulation.

Challenges and Future Directions

Despite their potential, several challenges remain in harnessing TLSs for clinical benefit. Standardized methods for TLS detection and quantification are lacking, and their dynamic nature complicates longitudinal assessment. Furthermore, not all TLSs are beneficial—some may foster immunosuppressive microenvironments in certain cancers. Future research should focus on deciphering the molecular cues governing TLS function and optimizing strategies to manipulate them therapeutically.

Conclusion

Tertiary lymphoid structures are increasingly recognized as critical regulators of antitumor immunity, with profound implications for cancer prognosis and treatment response. Their ability to shape the tumor immune landscape makes them valuable biomarkers and therapeutic targets. As our understanding of TLS biology deepens, integrating TLS assessment into clinical practice could refine immunotherapy selection and improve patient outcomes. Continued research into their induction and maintenance will be essential for unlocking their full therapeutic potential.

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