INSIGHTFUL research highlights a significant association between tertiary lymphoid structures (TLS) and response to immune checkpoint inhibitors (ICI) in Merkel cell carcinoma (MCC), offering new insights into how the spatial organisation of immune cells within tumours may influence treatment outcomes.
TLS are ectopic lymphoid aggregates that form within or around tumours and have been linked to prognosis and immunotherapy response in several cancers. However, their relevance in MCC, a rare but aggressive neuroendocrine skin cancer, has remained unclear. Moreover, existing studies have varied widely in how TLS maturity and functionality are defined. To address these gaps, the authors applied spatial proteomics to examine TLS characteristics at single-cell resolution in MCC patients treated with immunotherapy.
Spatial Organisation of Tertiary Lymphoid Structures
The study analysed 24 TLS from tumour samples of 13 patients with MCC who received the anti–PD-L1 antibody avelumab. Using the PhenoCycler platform with 16 oligonucleotide-labelled antibodies, the researchers performed high-dimensional immune profiling. Machine learning was used to classify tumour and immune cell populations, followed by spatial single-cell analyses, including cellular neighbourhood and cell–cell correlation assessments.
The results showed that TLS presence was strongly associated with clinical outcomes. A higher number of TLS correlated positively with both overall survival and response to ICI therapy (p=0.0274). Importantly, responders to avelumab had significantly more TLS located within the tumour compared with non-responders (p=0.0043).
Beyond TLS quantity, the study revealed striking differences in TLS architecture between responders and non-responders. In functional TLS from responder cases, T cells densely infiltrated B cell clusters and extended toward follicular dendritic cells, suggesting active immune crosstalk. CD4-positive T cells adjacent to CD8-positive T cells frequently expressed PD1, a marker of immune activation and checkpoint engagement. In contrast, TLS in non-responders were characterised by high B cell density but poor T cell infiltration into B cell zones, with T cells largely confined to peripheral regions.
Potential Role of TLS in Treatment Stratification
The authors conclude that both the number and spatial organisation of immune cells within TLS are key determinants of immunotherapy efficacy in MCC. These findings suggest that evaluating TLS functionality, rather than maturity alone, could improve prediction of ICI response and inform future biomarker development. Larger studies will be needed to validate these observations and explore their potential clinical application.
Reference
Nakamura M et al. Spatial Proteomics of Tertiary Lymphoid Structures Reveals Correlation with Immunotherapy Response in Merkel Cell Carcinoma. Br J Dermatol. 2025;DOI:10.1093/bjd/ljaf525.
