An IHC-derived TLS-CD8-macrophage immune niche score predicts major pathological response to neoadjuvant...

Neoadjuvant chemoimmunotherapy improves pathological response in resectable non-small cell lung cancer (NSCLC), but response remains heterogeneous. PD-L1 tumor proportion score (TPS) incompletely captures spatial immune contexture. We developed and cross-center validated an immunohistochemistry (IHC)-derived equal-weight immune niche score integrating tertiary lymphoid structure (TLS) maturity, CD8-TLS proximity, CD8/FOXP3 balance, CD163/CD68 ratio, and PD-L1 TPS.

This two-center retrospective cohort included 326 patients with resectable NSCLC treated with neoadjuvant chemoimmunotherapy. The model-development cohort included 188 patients, and an institution-level external-validation cohort within the same regional medical system included 138 patients. The primary endpoint was major pathological response (MPR). Model performance was evaluated using discrimination, calibration, decision curve analysis, and ablation analysis. Sensitivity analyses tested alternative CD8-TLS thresholds, ICI-agent subgroups, missing-data approaches, Granzyme B incorporation, and alternative weighting. Exploratory analyses assessed event-free survival (EFS), overall survival (OS), interobserver reproducibility, and asthma-related pulmonary safety.

Overall, 146 patients (44.8%) achieved MPR and 42 (12.9%) achieved pathological complete response. MPR tumors had higher TLS maturity, CD8+ cells within 50 μm of TLS, CD8/FOXP3 ratio, PD-L1 TPS, lower CD163/CD68 ratio, and higher immune niche score. In external validation, the score achieved an AUC of 0.732 (95% CI, 0.648-0.816), compared with 0.564 for the clinical model, 0.635 for PD-L1 alone, 0.613 for clinical + PD-L1, and 0.692 for XGBoost, with acceptable calibration. CD8-TLS proximity (OR 1.68, 95% CI 1.03-2.79), CD163/CD68 ratio (OR 0.66, 95% CI 0.48-0.91), and the composite score (OR 2.72 per 1 SD, 95% CI 2.05-3.69) were independently associated with MPR. Performance was stable across sensitivity analyses. Exploratory EFS was more favorable in the high-score group. Asthma history was not independently associated with MPR but was associated with higher composite pulmonary adverse-event rates.

This transparent IHC-derived TLS-CD8-macrophage immune niche score showed moderate cross-center validation performance for MPR prediction after neoadjuvant chemoimmunotherapy in resectable NSCLC, while remaining pathologically interpretable. It may complement PD-L1 TPS for response stratification, pending broader multicenter and prospective validation.