Divergent Tumor Immune Microenvironment and Response to Neoadjuvant Chemoimmunotherapy in Resectable Non-Small Cell Lung Cancer: A Single-Arm Phase II Trial.

Abstract

Neoadjuvant chemoimmunotherapy improves outcomes in resectable non-small cell lung cancer (NSCLC), yet the spatial immune features associated with treatment response remain unclear. In this single-arm phase II trial (NCT05383716), patients with resectable NSCLC received neoadjuvant pembrolizumab plus platinum-based chemotherapy, followed by surgery and adjuvant immunotherapy. The primary endpoint was major pathological response (MPR). Digital spatial profiling was performed on resected tumors and paired draining lymph nodes from 22 patients, with additional tumor samples collected for validation. Among 80 enrolled patients, 55 underwent surgery, achieving an MPR rate of 37.5% and a pathological complete response rate of 26.3%. Grade 3-4 treatment-related adverse events occurred in 26.3% of patients. Spatial transcriptomics showed that MPR tumors were enriched for T- and B-cell activation pathways and infiltration of CD8+ T cells, B cells, plasma cells, and T-follicular helper cells, whereas non-MPR tumors exhibited stress adaptation and immune suppression signatures. Two immune phenotypes were identified within MPR samples: myeloid-enriched (ME) and lymphoid-enriched (LE) subtypes. The LE subtype was associated with improved response and survival in validation cohorts, whereas higher ME scores showed a trend toward poorer survival. An 18-gene LE signature was developed as a potential biomarker for adjuvant immunotherapy benefit. Neoadjuvant pembrolizumab plus chemotherapy demonstrated encouraging efficacy and manageable safety in resectable NSCLC. Spatial profiling identified distinct immune phenotypes associated with response and may inform patient stratification for adjuvant therapy.