Abstract 6148: Immunogenomic landscape of tumor-infiltrating B and plasma cells in early-stage lung adenocarcinoma

Abstract Lung adenocarcinoma (LUAD) is the leading cause of cancer-related deaths in lifetime smokers. Relative to recent advances in immunotherapy of advanced-stage LUAD, there are very limited strategies for early immune-based treatment or interception of the malignancy in its primitive stages. This is largely due to a poor understanding of the roles and functional phenotypes of distinct immune cell subsets and how they evolve early in LUAD pathogenesis. For instance, while T cells have been a central focus of cancer immunopathology and immunotherapy, the roles of tumor-infiltrating B and plasma cells (TIBs) in the activity of the adaptive immune response along the pathogenic course of solid tumors such as LUAD are extremely poorly understood. To fill these voids, we conducted pan-cancer single-cell RNA sequencing (scRNA-seq) analysis of TIBs using public and in-house cohorts of >15 cancers and matched normal samples. We found that fractions of TIBs, including plasma cells (PCs), were evidently high in the tumor microenvironment (TME) of LUADs, particularly in smokers. We then performed multi-region paired scRNA-seq and single-cell B cell receptor sequencing (scBCR-seq) of tumors and three matched normal lung (NL) tissue samples with varying spatial proximity from each of the tumors of 16 early-stage LUAD patients. Fractions of TIBs including PCs and memory B cells were immensely increased in the TME of early-stage LUADs compared to uninvolved NL, and conversely, the abundance of naïve B cells was markedly decreased. TIB fractions were progressively increased along the pathologic continuum of NL, premalignant lesions (PMLs), up to invasive LUAD. Consistently, expression of the B cell chemotactic CXCL13 - CXCR5 axis in T cells and TIBs, respectively, was increased in both PMLs and LUADs relative to NL. Simultaneous scBCR-seq revealed markedly reduced clonality of BCR repertoires in LUAD compared to NL. Multi-region NL tissues showed progressively increasing BCR clonotype diversity and immunoglobin somatic hypermutation (SHM) with increasing proximity to tumors. BCR clonality was strikingly lower in smoker LUADs relative to non-smoker tumors as well as progressively attenuated with increasing pathologic stage. TIBs in the LUAD TME were mostly composed of terminally differentiated IgA+ or IgG+ PCs and memory B cells with an immunosuppressive phenotype. To understand how TIBs shape the LUAD TME, we also profiled interactions of TIBs with other TME cell components and identified TIB subsets showing strong co-occurrence patterns with immunosuppressive T cell subsets. By comprehensively defining transcriptional profiles, SHM and antibody repertories, as well as cellular interactions of TIBs at single-cell resolution, our results map out the geospatial landscape of TIBs in early-stage LUAD and provide a valuable resource to leverage targets for innovative immunomodulatory strategies. Citation Format: Dapeng Hao, Guangchun Han, Ansam Sinjab, Lorena Gomez Bolanos, Rossana Lazcano Segura, Enyu Dai, Luisa Maren Solis Soto, Edwin Parra, Jennifer Wargo, Stephen Swisher, Tina Cascone, Boris Sepesi, Junya Fujimoto, Steven Dubinett, Ignacio Wistuba, Christopher Stevenson, Avrum Spira, Humam Kadara, Linghua Wang. Immunogenomic landscape of tumor-infiltrating B and plasma cells in early-stage lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6148.