The Single-Cell Immunogenomic Landscape of B and Plasma Cells in Early-Stage Lung Adenocarcinoma

Abstract

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.

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

“…By contrast, B cell signatures were significantly elevated in both subtypes, but to a greater degree in LUAD than in LUSC (Extended Data Fig. 6a,b ), in agreement with a recent report 6 . Both TLS and B cell signatures were inversely proportional to tumour purity (Extended Data Fig.…”

“…Total tumour mutational burden (TMB) correlated significantly with BCR repertoire diversity and IgG frequency in individual tumour regions from patients with LUAD, but not with TLS or B cell signatures (Extended Data Fig. 9a ), in line with prior reports 6 . Similarly, no significant effects of smoking status or TP53 , EGFR or KRAS mutations were observed, with the possible exception of reduced TLS and B cell signatures in tumour regions with subclonal TP53 mutations in this cohort (Extended Data Fig.…”

“…Similarly, no significant effects of smoking status or TP53 , EGFR or KRAS mutations were observed, with the possible exception of reduced TLS and B cell signatures in tumour regions with subclonal TP53 mutations in this cohort (Extended Data Fig. 9b ), although marked elevation of plasma cells in patients with LUAD with a smoking history was recently reported 6 .…”

“…Predicting responses to immune checkpoint blockade (ICB) remains a challenge, with 70% of patients failing to respond despite high mutational burden 4 . Recent studies have identified tertiary lymphoid structures (TLS), ectopic lymphoid organs containing B and T cells in the tumour-adjacent stroma, as strong predictors of ICB response in several cancer types 1 , 2 , including in lung adenocarcinoma (LUAD) 5 , 6 , where their presence and density independently correlate with longer overall and recurrence-free survival 1 , 2 . However, cause-and-effect relationships of the associations between TLS, patient survival and immunotherapy response have not yet been established 1 , 2 .…”

Identification of an immune subtype-related prognostic signature of clear cell renal cell carcinoma based on single-cell sequencing analysis

“…Unlike traditional RNA sequencing, SCQ will help to understand the differences between different cells at the gene and gene expression levels during disease progression ( 15 , 16 ). SCQ is now widely used in the study of various diseases, and results have been achieved ( 17 , 18 ).…”