WCLC 2025 - Posters & ePosters-P2.06.17 Cellular Heterogeneity and Tertiary Lymphoid Structure Dynamics Predict Overall Survival in Immune Checkpoint Therapy-Treated NSCLC Patients

P2.06.17 Cellular Heterogeneity and Tertiary Lymphoid Structure Dynamics Predict Overall Survival in Immune Checkpoint Therapy-Treated NSCLC Patients

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This study addresses the challenge of predicting overall survival (OS) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI) by integrating tumor microenvironment (TME) cellular heterogeneity with tertiary lymphoid structure (TLS) dynamics using bulk RNA-sequencing data. The researchers employed a Cellworks-developed algorithm to deconvolute cell type proportions and gene expression from bulk transcriptomic data. They enhanced this with a TLS Score based on 34 key genes reflecting TLS maturity and cellular interactions.<br /><br />A Cox proportional hazards model was trained on a cohort of 63 advanced NSCLC patients (SU2C-MARK) to predict OS using TME cell proportions and the TLS score, and then validated on an independent cohort of 66 ICI-treated NSCLC patients. The integrated model showed strong predictive power in both training (HR=0.36, C-index=0.768, p<0.001) and validation cohorts (HR=0.66, C-index=0.628, p<0.001). When patients were dichotomized by model score, significant survival differences were observed (median OS 12 vs. 30.8 months, HR=0.45, p=0.025).<br /><br />Key findings revealed that intermediate-stage TLS, not just fully mature TLS, provides survival benefits when present in an immune-stimulatory milieu. However, high levels of neutrophils, SPP1M2-like macrophages, and myeloid-derived suppressor cells (MDSCs) within the TME could negate this benefit, underscoring the importance of immune balance over TLS morphology alone. The results suggest that combined assessment of TLS dynamics and cellular composition offers improved insights into ICI responsiveness.<br /><br />The study concludes that integrating structural and cellular features of the TME predicts NSCLC patient survival under immunotherapy, but further validation in larger cohorts is required for clinical application.

Asset Subtitle

James Wingrove

Meta Tag

Speaker James Wingrove

Topic Pathology and Biomarkers

Keywords

non-small cell lung cancer

immune checkpoint inhibitors

tumor microenvironment

tertiary lymphoid structure

bulk RNA-sequencing

cellular heterogeneity

Cox proportional hazards model

overall survival prediction

immune-stimulatory milieu

myeloid-derived suppressor cells