Genomic and immune heterogeneity of multiple synchronous lung adenocarcinoma at different developmental stages

Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyzed 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation revealed clonally independent tumors with convergent evolution driven by shared driver mutations. However, tumors from the same individual exhibited minimal shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observed a shift in T cell phenotypes characterized by increased Tregs and exhausted CD8 + T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibited greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.