Spatial and maturational characterisation of tertiary lymphoid structures predicts immunotherapy response in extensive‐stage small cell lung cancer
Haoyu Wang, Xiaoling Shang, Yuanzhu Jiang, Chenglong Zhao, Zhenxiang Li, Chufeng Zhang, Qinhao Xu, Shanshan Du, Jiamao Lin, Haiyong WangAbstract
Objectives
Extensive‐stage small cell lung cancer (ES‐SCLC) remains an aggressive malignancy with limited durable responses to immune checkpoint inhibitors (ICIs) and no established predictive biomarkers. This study aimed to evaluate the prognostic and predictive value of tertiary lymphoid structures (TLSs) in patients with ES‐SCLC receiving ICI‐based therapy.
Methods
In this multicenter retrospective study of 180 treatment‐naïve ES‐SCLC patients subsequently receiving ICI‐based therapy, TLSs were systematically evaluated using H&E staining, multiplex immunofluorescence, and spatial analysis to determine their prognostic and predictive value.
Results
TLSs were identified in 22.2% of cases and independently associated with improved overall survival (OS) in both univariate (HR = 0.365, 95% CI: 0.217–0.613, P < 0.001) and multivariate (HR = 0.337, 95% CI: 0.199–0.569, P < 0.001) analyses. Crucially, TLS maturation status was associated with clinical outcomes, as patients with mature TLSs containing CD21 + follicular dendritic cells and organized germinal centers experienced significantly longer survival than those with non‐mature TLSs ( P = 0.0049). Beyond mere presence, responders to ICIs exhibited distinct spatial characteristics, including higher TLS densities, denser immune infiltration, and shorter distances between TLS‐resident CD20 + B cells, CD3 + T cells, and tumor cells, suggesting that immune–tumor spatial organization within TLSs reflects functional antitumor engagement.
Conclusion
TLS maturation and spatial architecture may serve as candidate tissue biomarkers associated with clinical outcomes in ICI‐treated ES‐SCLC, warranting prospective validation alongside SCLC molecular subtyping.