Deciphering tumor-intrinsic and immune characteristics in resectable non-small cell lung cancer treated with neoadjuvant pembrolizumab and chemotherapy.

BACKGROUND: Neoadjuvant chemo-immunotherapy (NCIT) aims to improve surgical and survival outcomes of non-small cell lung cancer (NSCLC) patients. However, the clinical application of NCIT still necessitates coordinated immune and molecular biomarker testing. METHODS: We conducted whole transcriptome sequencing on baseline and surgical samples from 26 patients with stage II-III resectable NSCLC who underwent neoadjuvant pembrolizumab plus chemotherapy followed by surgery. Gene expression and immune cell characteristics in the tumor microenvironment were assessed in relation to pathological complete response (pCR) and patient prognosis. RESULTS: Baseline pCR tumors were characterized by increased expression of genes related to antigen presentation (HLA-C, HLA-E, B2M), immune checkpoint regulation (BTN3A1, CD274), and innate immunity (HMGB1). Surgical samples from pCR patients showed elevated expression of immune-related genes (IGHD, LILRA6, and ICOSLG) but reduced CEACAM6 expression linked to cell adhesion and tumor progression. During NCIT, plasma cells and resting NK cells declined consistently across pathological groups. Non-pCR patients exhibited greater leukocyte-mediated immunity and higher CD8 + T cell infiltration (P < 0.01) post-treatment, suggestive of a sustained anti-tumor immune response. Baseline MGAT5B expression predicted pathological response (area under the curve: 0.86) and was associated with shorter disease-free survival (DFS; P = 0.03), with a consistent trend for overall survival (OS). Higher CEACAM6 expression in surgical samples was associated with both shorter DFS and OS (P = 0.03 and P = 0.04, respectively). The clinical relevance of MGAT5B and CEACAM6 expression for predicting NCIT response and prognosis was further validated in a clinical validation cohort. CONCLUSIONS: Our study identified molecular biomarkers for pathological and survival outcomes, which may inform optimal treatment decision-making, guide postoperative therapy, and improve survival outcomes for stage II-III patients with resectable NSCLC.