Tertiary Lymphoid Structures in Cancer Immunology

Tertiary lymphoid structures (TLS) are ectopic, organised aggregates of immune cells that develop at sites of chronic inflammation, including within tumours. Architecturally reminiscent of secondary lymphoid organs, TLS comprise distinct B-cell follicles, T-cell zones, follicular dendritic cell networks and high endothelial venules, creating local niches for antigen presentation, lymphocyte activation and germinal centre reactions. Their presence in diverse cancer types has been linked to improved patient survival and enhanced response to immunotherapy, reflecting the capacity of TLS to orchestrate both humoral and cellular anti-tumour immunity. However, TLS are heterogeneous in maturity, cellular composition and spatial distribution, which can influence whether they support tumour control or, in some settings, promote immunosuppression. A deeper understanding of the signals that govern TLS neogenesis, organisation and functional polarization holds promise for harnessing these structures as prognostic biomarkers and as targets for strategies that convert immune-cold tumours into inflamed, therapy-responsive microenvironments.

Research from Nature Portfolio

Recent studies have elucidated the pivotal role of intratumoral B-cell compartments within TLS in driving effective immunotherapy. In lung adenocarcinoma models, local germinal centre responses were shown to generate antibodies against endogenous retroviral envelope proteins; these responses were amplified by immune checkpoint blockade and necessitated chemokine-mediated TLS formation for therapeutic efficacy. A comprehensive immune profiling of soft-tissue sarcomas revealed that tumours enriched for B-cell-rich lymphoid aggregates correlated strongly with improved survival and were predictive of beneficial outcomes following PD-1 blockade. In head and neck squamous cell carcinoma associated with viral infection, detailed analyses of germinal centre B-cell maturation within organised TLS demonstrated distinct phenotypic waves whose presence was linked to favourable prognosis, highlighting opportunities to modulate humoral immunity in combination with T-cell-focused therapies.

Tertiary Lymphoid Structures in Cancer Immunology publication trend

The graph below shows the total number of articles in tertiary lymphoid structures in cancer immunology across all publications each year (not limited to Nature Index journals).

Technical terms

Tertiary lymphoid structure (TLS): Transient, organised aggregates of lymphoid cells that form in non-lymphoid tissues under chronic inflammatory conditions, supporting local adaptive immune responses.

Germinal centre: A specialised microenvironment within lymphoid structures where B cells undergo proliferation, somatic hypermutation and affinity maturation to produce high-affinity antibodies.

High endothelial venule (HEV): A specialised post-capillary venule with cuboidal endothelial cells that facilitates lymphocyte entry from the bloodstream into lymphoid tissues or TLS.

Immune checkpoint blockade (ICB): Therapeutic inhibition of regulatory pathways in T cells (such as PD-1 or CTLA-4) to enhance anti-tumour immunity.

Tumour microenvironment: The complex milieu of cancer cells, stromal cells, immune cells, extracellular matrix and soluble factors that collectively influence tumour progression and therapy response.

References

1. Tertiary lymphoid structures in diseases: immune mechanisms and therapeutic advances. Signal Transduction and Targeted Therapy (2024).
2. Antibodies against endogenous retroviruses promote lung cancer immunotherapy. Nature (2023).
3. Tertiary lymphoid structural heterogeneity determines tumour immunity and prospects for clinical application. Molecular Cancer (2024).
4. Tailoring vascular phenotype through AAV therapy promotes anti-tumor immunity in glioma. Cancer Cell (2023).
5. B cells are associated with survival and immunotherapy response in sarcoma. Nature (2020).
6. B cell signatures and tertiary lymphoid structures contribute to outcome in head and neck squamous cell carcinoma. Nature Communications (2021).