CD8+ TILs in necrotic tumors after neoadjuvant immunochemotherapy predict outcomes in non-small-cell lung cancer patients

Abstract Neoadjuvant immunochemotherapy has shown promising results, with major pathologic response (MPR, ≤10% residual viable tumors [RVT]) as the primary outcome. However, %RVT showed limited predictive power in stratifying outcomes within the MPR and non-MPR groups. To identify a better prognostic marker, this study analyzed 200 non-small-cell lung cancer (NSCLC) samples after neoadjuvant PD-1 blockade combined with chemotherapy across three medical centers. Among these patients, 99 had necrotic regions in their residual lesions. We found that tumor-infiltrating lymphocytes in necrotic areas (nTILs) lose their cellular structure, but retained T-cell-specific antigens, making them detectable by immunohistochemistry. Regardless of PD-L1 status or lymph node metastasis, patients with high CD8 + nTIL density had significantly improved event-free survival (EFS) (hazard ratio [HR]: 0.08; 95% CI: [0.01–0.62]; p = 0.0019). Furthermore, CD8 + nTIL density improved prognostic predictions for patients within the MPR ( p = 0.017) and non-MPR groups ( p = 0.076). Radiological responses did not correlate with MPR, CD8 + nTIL density or EFS. 41.5% MPR cases were misclassified by radiological assessments. When compared with radiographic response and pathological response, CD8 + nTIL density outperformed these traditional parameters in approximating EFS. These findings demonstrate that the CD8 + nTIL density is a robust predictor of EFS in NSCLC patients treated with neoadjuvant immunochemotherapy and has great potential in guiding treatment decisions.