Decoding B-cell Signatures of Complete Pathologic Response to Perioperative Chemoimmunotherapy in Non-Small Cell Lung Cancer

Purpose: Complete pathologic response (CPR) correlates with long-term survival after perioperative chemoimmunotherapy (ChIO) in resectable non-small cell lung cancer (NSCLC). We provide a multiomic characterization of B cells and tertiary lymphoid structures (TLS) to dissect the immune landscape associated with CPR. Experimental design: We integrated B-cell receptor (BCR) repertoire profiling (n = 87 tissue, n = 25 blood), multiplex immunofluorescence (n = 67), and bulk (n = 15), spatial (n = 12), and single-cell transcriptomics (n = 15) from tumor tissue and blood (baseline, surgery, and at 6 months of adjuvant therapy) in 123 patients (NADIM/NADIM II trials, NCT03081689/NCT03838159). Results: CPR tumors exhibited a more clonal baseline BCR repertoire (AUC 0.775; P = 0.030) that was better conserved and reinvigorated during neoadjuvant ChIO. In blood, patients with CPR tumors displayed a repertoire enriched in class-switched clones (AUC 0.833; P = 0.008), characterized by higher diversity, lower clonality, and upregulation of activation-related transcriptional programs. Neoadjuvant ChIO was associated with the induction of B-cell-related genes within TLS regions and with higher TLS density at surgery compared with Ch (P = 0.034). TLS density was not associated with CPR (P = 0.129); however, mature TLS in CPR tumors were enriched in immune activation and antigen-presenting pathways, estimated T follicular helper cells, plasmacytoid dendritic cells, and plasma cells, whereas low B-cell regions from CPR tumors displayed higher inferred infiltration of CD8+ T cells, NK cells, and macrophages, with reduced neutrophils and Tregs. Conclusions: Patients with CPR tumors exhibit a preexisting and more mature B-cell response that develops further during neoadjuvant ChIO. Our findings link B-cell-related features to CPR and highlight BCR metrics as promising predictive biomarkers in NSCLC.