Abstract 6097: The role of B-cell receptor repertoire in lung squamous premalignant lesions

Abstract Objective: B cells and plasma cells (PCs) play a vital role in the pathogenesis of lung cancer and provide prognostic predictive value. However, the role of B cells in the bronchial premalignant lesions (PMLs), the precursor of lung squamous cell carcinoma, is poorly understood. Prior work has shown that progression of proliferative subtype, a PML molecular subtype enriched with bronchial dysplasia, to a higher histology grade is associated with downregulation of antigen processing and presentation. In this study, we seek to understand the role of B cells, PCs, and the B-cell receptor (BCR) repertoire in progression of the bronchial PML. Methods: We performed bulk targeted BCR sequencing on 69 endobronchial biopsies obtained from 29 subjects at high-risk for developing lung cancer. The Immcantation pipeline were applied to obtain the V(D)J germline segment assignment using the human reference from IMGT, clonal cluster assignment, and mutational load quantification for each BCR sequences by pooling all the BCR sequences from the same subjects. The clones with frequency less than 10-4 were filtered out. We then performed the repertoire analysis, such as clonality diversity, isotype switching frequency, and somatic hypermutation rate (SHM) rate at sample levels and investigated the association with transcriptional signature derived from bulk RNA-seq and the clinical progression of PMLs. Results: The B cell and PC transcriptional signatures and B cell chemoattractants gene expression are associated with progression in proliferative subtype PMLs. The number of BCR clones, the class switch from IgG3 to IgG1, and the mutational rates of total and CDR3 regions were positively correlated with the B cells and PCs transcriptional signatures. Among the 31 PMLs of proliferative subtype, regressive lesions showed higher proportions of IgG heavy chain usage, higher SHM rate in CDR3 and total BCR regions, and higher frequency of class switch from IgD/M to IgG and from IgG3 to IgG1. Biopsies within the same patient had a higher proportion of shared BCR clones when they were sampled at the same timepoint than when they were sampled from the same anatomic location at different timepoints. The preserved clones of BCRs at the same anatomic location over different times had higher clonality, more class switch from IgD/M to IgG or IgA and from IgG3 to IgG1, and increased SHM rates than the non-preserved clones. Conclusions: These results suggest B and plasma cells exert anti-tumor effects that prevent bronchial PMLs from progressing to higher grade lesions by switching to IgG1 BCRs and increasing SHM rates. Citation Format: Darren J. Chiu, Carter Merenstein, Marc Lenburg, Sarah Mazzilli, Jennifer Beane. The role of B-cell receptor repertoire in lung squamous premalignant lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6097.