Tumor-infiltrating B and plasma cells (TIBs) are prevalent in lung adenocarcinoma (LUAD), however they are poorly characterized. We performed paired single-cell RNA and B cell receptor (BCR) sequencing of 16 early-stage LUADs and 47 matching multi-region normal tissues. By integrative analysis of ~50,000 TIBs, we define 12 TIB subsets in the LUAD and adjacent normal ecosystems and demonstrate extensive remodeling of TIBs in LUADs. Memory B cells and plasma cells (PCs) were highly enriched in tumor tissues with more differentiated states and increased frequencies of somatic hypermutation. Smokers exhibited markedly elevated PCs and with distinct differentiation trajectories. BCR clonotype diversity increased but clonality decreased in LUADs, smokers, and with increasing pathologic stage. TIBs were mostly localized within CXCL13+ lymphoid aggregates and immune cell sources of CXCL13 production evolved with LUAD progression and included elevated fractions of CD4 regulatory T-cells. This study provides a spatial landscape of TIBs in early-stage LUAD.

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